Many years elapsed before the King of Spain, and the Council of the Indies made any serious effort to colonize Tierra Firme.  It wasn't until 1508,  four years after the Admirals voyage, that any attempt to colonize area it was attempted.

Herrera, the official historian of the Court, wrote that the king was very interested in having Tierra Firme colonized; but, at the time, he was preoccupied with the wars in Spain. The person most interested in colonizing the area, was Alonso de Ojeda. Unfortunately, he was not a rich man, and could not contract with the King, without the support of others. Juan de la Cosa, who had been with Columbus on some of his voyages, offered financial support. With the support of Juan Rodriquez de Fonseca , Bishop of Palencia, who managed of the Affairs of the Indies, he went to Court.

His greatest asset was the loyalty of the old pilot Juan de la Cosa. , Peter Martyr, one of the most trustworthy of the contemporaneous chroniclers of the Discovery, says that the navigators of the day valued above all other maps those made by de la Cosa "to whom these tracks were as well known as the chambers of his own house." He had sailed more miles in the Caribbean Sea than even the great Almirante. He had a sagacious head and the quiet sort of bravery which was badly needed to balance the dashing impetuosity of Ojeda. 

There was another applicant for the privilege of colonizing Tierra Firme, Don Diego de Nicuesa. He had the advantage not only being richer than Ojeda, but also the more polished. He held the office of The Royal Carver, wore the fanciest clothes ever seen in Madrid, was very popular with the ladies at Court, and was a gentleman of unquestioned integrity and valor. But he lacked  training for the hard work that was to come. There is not very little good that could be said of Nicuesa ability to lead men during a crises. He proved to be a stubborn fool, who mistrusted his men, and succeeded in turning his friends against him. He set aside the Royal Carving Knife for the sword of the conqueror.

For a long time Merit and Favoritism balanced each other in the mind of the king. Not being able to make a choice between them, he appointed them both. Nicuesa was to govern Castilla del Oro, from Cape Gracias a Diós to the border of Nueva Andalusia. Ojeda was given Nueva Andalusia from Cape de la Vela to the domains of Nicuesa. The dividing line between their jurisdictions was left for them to fight out.

In the fall of 1509, five years after Columbus had returned from Panama, the two governors met in Española and started quarreling right away. The king had further complicated matters, by giving them, as a joint source of provisions, the Island of Jamaica. This upset the governor of Española, Diego Colon, the son of the Great Admiral. Diego claimed all lands discovered by his father, which included Jamaica. This made him so hostile to the two new governors, that instead of helping them with ships and men, as the king had ordered, he did all he could to hinder and impede them. He also did everything he could to fan the fire of jealousy between them.

With all of the fighting between themselves, Ojeda soon lost his cool and challenged Nicuesa to a duel. With the mediation of Juan de la Cosa, bloodshed was averted and they agreed to accept the Darien River, now called the Atrato River, as the boundary between their provinces.

The truce that existed between them was very precarious. Nicuesa, being the more affluent of the two, was able to outbid Ojeda for ships and equipment. This was  counterbalanced by Ojeda's experience in the area, his reputation and personal charisma  attracted the best and most able of the volunteers. Among them were two who would later paint their names in letters of blood and fire on the chronicle of the Americas, Hernado Cortes and Francisco Pizarro. Ojeda was able to enlist the Bachelor of Law, Martin Fernandez de Enciso to his side. This attorney had amassed a fortune in the few years of colonial practice. But he had not realized the fact that it is easier to get money from adventurers than by adventures. Like so many another he fell under Ojeda's  charm. Ojeda promise to make him "Alcalde Major", Chief Justice of the soon to be conquered vice-royalty of Nueva Andalusia, and he turned offered Ojeda his fortune.

On November 12, 1509, Ojeda set sailed from Española, with two ships, two brigantines, three hundred men and twelve brood mares. Hernando Cortes was not able to sail with him, due to a wound in his knee and was left behind. On November 14, 1509, Nicuesa set sail with two large ships, two brigantines, a caravel, seven hundred men and six horses. Nicuesa led a better equipped and lager expedition. His force was made up mostly of men fresh from Spain, lacking experience, and not  hardened for the work before them.

The Bishop of Palencia had given Ojeda, before he left Spain, a miraculous portrait of the Virgin Mary that was to protect him. He carried it on his person, at all times, in the belief that it made him invulnerable, and no harm would come to him, as long as he had it. There were many witnesses which make it possible to believe that he actually lived through the innumerable adventures during his life time.

Shortly after leaving Española, Ojeda's fleet reached his unconquered, new vice-royalty, near the present city of Cartagena, Colombia. He went ashore with part of his force to take possession of the land, and establish his authority in the area. He proceeded to wave the Spanish flag, erect a cross at the point where he set foot on dry land. The Spaniards that had previously visited this coast had come to trade. The Indians in the area, came to the shore with hospitable intention and willing to trade. Having satisfied his own idea of taking possession, Ojeda turned his attention to the natives. He ordered some of his friars, who had come to look after the spiritual welfare of the new domains, to read aloud the following proclamation. This curious treatise had been drawn up by learned divines at home and with slight alterations was employed by the other Conquistadors under similar circumstances:

How much the natives understood of this discourse in Spanish is unknown. We know that something was understood, since they replied with great dignity that they were satisfied with their own chiefs and were ready to protect their wives, children and land.

On the open beach, the Spaniards quickly defeated the natives that resisted. The Spaniards had not yet learned the danger of following the natives into the jungle, nor had they learned the horror of their poisoned arrow. After defeating the natives on the beach, Juan de la Cosa urged Ojeda to be content with his victory. He urged the importance of finding a suitable place for their settlement and had established themselves before continuing the battle against the natives. Ojeda's nature to not to be cautious and he was excited after defeating the natives on the beach. He ordered the pursuit of the natives into the jungle. After about an hour, they came to a large Indian village. Immediately, the Spaniards scattered in all directions, looking for booty. At that point, the natives who had taken refuge in the jungle, attacked them. The Spaniards had let down their guard and most of them fell during the first surprise attack. Juan de la Cosa rallied a few of them and regrouped to offered some resistance. Only one of this group escaped. Ojeda also escaped into the jungle. Separated from his men he got lost in this strange and foreign land. Without food and in constant danger of discovery he struggled through the dense underbrush. He finally reached the seaside where he was found by his men in an almost dying condition. The sailors left on shipboard had become desperate at the long absence of the landing party. Just when things were at their darkest some sails came up over the horizon, it was the Nicuesa's fleet.

The two governors had parted Española in anger, and Ojeda feared that Nicuesa would take advantage of his distress. But Nicuesa. in the only noble incident related to him, sent word that "A Spanish hidalgo does not harbor malice against a prostrate foe." He sent a party of men to help Ojeda avenge the death of Juan de la Cosa and his men. They surprised the Indians, who were feasting in their village, in celebration of their victory, and massacred every last man, women and child. The blood lust of the Spaniards was whetted by the sight of the corpse of de la Cosa, horribly bloated and discolored as a result of the poisoned arrows. Nicuesa's men share of the booty was over thirty-five thousand dollars.

Ojeda then sailed on to the Gulf of Darien, the western boundary of his province, and disembarked on the eastern shore of the gulf. In memory of Juan de la Cosa and as a protective charm, he named the settlement, San Sebastian, after the saint who died from arrow wounds. This was the first European settlement on the American continent. He then sent his fastest ship back to Española, with some of the booty and glowing letters to Enciso, urging him to hurry up with the much needed reinforcements and supplies.

Initially, the small settlement of San Sebastian, attempting to establish itself, relied on the supplies and food that was brought with them. Their major problem was the poison, which the natives tipped their arrows with. So deadly was the venom that the slightest scratch meant a horrible death. Herrera gives interesting details as to the method of its manufacture:

Today, it is hard to believe that this was the real receipt for this powerful poison, but it does illustrate how fearful the Spaniards were of the natives arrows in the region.

As time passed, and the colony consumed the limited food they had brought from Española, it started to get scare. All along, they were waiting for Enciso's ships, with provisions. Enciso never left Española until September, 1, 1510, 8½ months after Ojeda. Had Enciso not taken so long, the settlement of San Sebastian may still exist and have the distinction of being the oldest continuously inhabited city on the main land of America. But the colonist were going hungry, and they dared not wander too far from their small community and fortifications. Anybody that got to close to the jungle, was immediately attacked by the natives and their deadly poison arrows. This fear of the natives, prevented them from going out to forage for food, or planting any type of crop, to supplement their diet. 

As far as battle was concerned, Ojeda was still leading a charmed life. His picture of the Virgin was still protecting, such that, he had never been wounded or bled in battle. His confidence in the powers of the Virgin was such, that was always in the front of any skirmish with the native. After a while, event the natives began to believe that his life was charmed. During one of the many skirmishes, the natives held their best archers in reserves. When Ojeda approached their hiding place, the four Indians shoot at him. Three arrows missed him, but the fourth arrow, went right through his thigh, wounding him for the first time in battle.

This incident, Ojeda's wounding, really upset the whole colony and it was thrown into despair. They felt that the blessed Virgin had taken away her protection, and the colony was doomed. During the whole time they were in Nueva Andalusia, nobody had ever survived the wound of a poison arrow. Those that were not killed outright, suffered a slow and painful death. The accepted practice of the time was the amputation of the limb. But Ojeda was a fighter, and this was not going to get him down nor did he want to lose his leg. He ordered their surgeon to cauterize the wound thoroughly with a hot iron. The surgeon did not want to do it, but Ojeda threatened to execute him if he did not. The surgeon ran a white-hot iron rod through his leg, and then applied whit-hot iron plates to the entrance and exit wound. This all took place without any form of anesthesia or being held or tied. Such was Ojeda's fortitude and although this sounds impossible, you have to remember that these men were born to the saddle and the hard life of battle, and to show signs of pain, was not in their nature. The burning did so much damage, that they had to consume a whole barrel of vinegar, imbibing sheets and wrapping him in them. Fortunately, the arrow had gone completely through his thigh, and little of the poison was deposited in his leg. Ojeda took some time to recover from his wound, (the arrow wound and the burning iron) giving some historians to believe that he was lucky to have been shoot with a non-poisoned arrow.

After this incident, the settlement became very discouraged. The natives were making it impossible to go out side their stockade, even to get fresh water. Has disperse was setting in, they spotted a ship approaching from a distance. They thought that it was Enciso, coming with their reinforcements. But, once again, whey were faced with disappointment when it was not Enciso.

The brigantine that dropped anchor close by, was under command of Bernardino deTalavera, a privateer, who was looking for booty on the northern coast of Tierra Firme and San Sebastian. When the brigantine, which Ojeda had sent, loaded with the first gold and pearls from his new province, reached Santo Domingo, the word spread of the treasures and success of the new colony. Talavera, wanting in on the booty, collected a gang of thieves and cut-throats and marched overland to a small cove where a Genoese brigantine was taking on lumber. They murdered the crew and set sail to join Ojeda. Talavera's crew consisted of 70 other desperados and was carrying a cargo of Cassava bread and meat. They expected that they would become rich, just as Ojeda's men were, by trading or stealing from the natives. They had no idea about the hardships that the colony had suffered, or was in at the time.

The small amount of food that they brought, was an immediate relief for the famine at San Sebastian. They did not have enough to provide total relief. When the pirates realized the difficulties ahead, the poisoned arrows, hunger, no treasures, they decided to return to Española, instead of staying in Nueva Andalucia.

Ojeda decided to sail with Talavera to Española with the hope of seeding up Enciso with the reinforcements and supplies for San Sebastian. He left Francisco Pizarro in charge of what was left of his forces, with instructions to remain at San Sebastian for fifty days. If Enciso or Ojeda did not return with the needed reinforcements, they were free to abandon San Sebastian, and sail back to Española in the two remaining brigantines. These two ships had been attacked by the Teredo worms, and in very poor conditions.

Ojeda, took with him on the trip back to Santo Domingo, all of the treasures that they have been able to take from the natives. He freely informed his host, as to the contents of his luggage, and said that he intended to buy more provisions in Española and return to San Sebastian. No sooner were they out of sight of land, when Talavera took him prisoner, and confiscated all of the gold and pearls Ojeda had. Ojeda tried to fight with his captors, and challenged them; but they refused to fight him. They were aware of his reputation, as a man that never lost a fight, and was an excellent swords man.

Soon afterwards, they were hit by a hurricane, and since Talavera was a poor captain and navigator, they were forced to release Ojeda, so that he could save the ship in the storm. He was able to keep the ship afloat, long enough to get to the western end of Cuba, where they ran aground, losing the ship and treasure. Cuba, at this time, was still an unconquered island, and they had to endure constant attacks by the native and hunger. They marched 400 miles eastward, stumbling through swamps and cutting their way through the jungle. After several months in Cuba, there were only about a dozen of them still alive. They were able to get a message to Jamaica about their predicament and Pánfilo de Narváez came to their rescue in a caravel. Talavera was hanged in Jamaica for piracy..

By the time he finally reached Santo Domingo, Ojeda was unjustly thrown into prison and eventually set free. He died in a hospital in Santo Domingo in 1515 from complications from his old wound, by the poison arrow. When he died, he was so poor, and broken in spirit, that he did not have enough money to get buried with. With his last breath, he requested that his body be laid to rest in the monastery of San Francisco near the portal.

After Ojeda left San Sebastian, the settlers, under the command of Pizarro, waited for Enciso or Ojeda to return with supplies. They were not aware that they would never receive any help from Ojeda, who was now stranded in Cuba. During this time, their group was getting smaller and smaller. On the Fiftieth days after Ojeda left, they were still without provision, growing weaker, and dieing off. Since there were still 70 colonist alive, and they did not all fit into the two ships that were available. Pizarro asked for volunteers to remain behind so that the rest could escape, with the promise of returning to get them later. There were no volunteers so they decided to wait a little longer, with the expectation that famine, sickness and the poisoned arrows of the natives, would eventually reduce their number, so the could all fix on the boats.  This took place, shortly after, so they loaded what ever provisions there were left on the ships. The four remaining horses were killed, salted and loaded onboard.

Pizarro commanded on of the brigantines, and Valenzuela was in command of the other. As soon as the got outside of the harbor, the encountered a storm. Valenzuela's already weakened brigantine fell apart in the rough water, and all hands were lost. Pizarro's boat was close by, but could not save any of the men from the stricken vessel.

There were 30 men in Pizarro's worm eaten boat, fighting for their lives against the elements, when they were sighted by Enciso's ships that were coming to reinforce the community of San Sebastian.