Hojeda, accompanied by Francis Pizarro, departed from the island Beata, standing to the southward, and arrived in a few days at Carthagena, which is called Caramari by the Indians. The natives of that place were then in great confusion, and ready to oppose the Spaniards, because of the injuries which had been done them by Christopher Guerra and others, who had carried away many of the natives for slaves not long before. The natives of this coast were of large stature, the men wearing their hair down to their ears, while the women wore theirs long, and both sexes were very expert in the use of bows and arrows. Hojeda and Cosa had some religious men along with them, their Catholic majesties being very desirous to have the Indians converted to Christianity; and having some natives of Hispaniola along with them as interpreters, they tried by their means to persuade the Indians to peace, leaving off their cruelty, idolatry, and other vicious practices; but they were much incensed against the Spaniards, on account of the villanous conduct of Guerra, and would by no means listen to any peace or intercourse. Having used all possible methods to allure them to peace and submission, pursuant to his instructions, he had also orders to declare war and make slaves of them, in case of their proving obstinate. He had at first endeavoured to procure gold from these natives in exchange for Spanish toys; but as they were fierce and refractory, Cosa recommended that they should establish their colony at the bay of Uraba, where the natives were more gentle, after which they could return to Carthagena better provided to overcome the resistance of the natives. Hojeda, having been engaged in many quarrels and encounters, both in Spain and Hispaniola, in all of which he had come off without hurt, was always too resolute and fool hardy, and would not listen to the salutary advice of his companion. He therefore immediately fell upon the natives who were preparing to attack him, killed many, seized others, and made booty of some gold in their habitations. After this, taking some of his prisoners as guides, he marched to an Indian town, four leagues up the country, to which the natives had fled from the skirmish at the shore, and where he found them on their guard in greater numbers, armed with targets, swords of an extraordinary hard wood, sharp poisoned arrows, and a kind of javelins or darts. Shouting their usual war cry, St Jago, the Spaniards fell furiously upon them, killing or taking all they met, and forcing the rest to fly into the woods. Eight of the natives who were not so expeditious as their fellows, took shelter in a thatched hut, whence they defended themselves for some time, and killed one of the Spaniards. Hojeda was so much incensed at this, that he ordered the house to be set on fire, in which all these Indians perished miserably. Hojeda took sixty prisoners at this town, whom he sent to the ships, and followed after the Indians who had fled. Coming to a town called Yarcabo, he found it deserted by the Indians, who had withdrawn to the woods and mountains with their wives, children, and effects, on which the Spaniards became careless, and dispersed themselves about the country, as if they had no enemies to fear. Observing the careless security of the Spaniards, the Indians fell upon them by surprise while they were dispersed in small parties, and killed and wounded many of them with their poisoned arrows. Hojeda, with a small party he had drawn together, maintained the fight a long while, often kneeling that he might the more effectually shelter himself under his target; but when he saw most of his men slain, he rushed through the thickest of the enemy, and running with amazing speed into the woods, he directed his course, as well as he could judge, towards the sea where his ships lay. John de la Cosa got into a house which had no thatch, where he defended himself at the door till all the men who were with him were slain, and himself so sore wounded with poisoned arrows that he could no longer stand. Looking about him in this extremity, he noticed one man who still fought with great valour, whom he advised to go immediately to Hojeda and inform him of what had happened. Hojeda and this man were all that escaped of the party, seventy Spaniards being slaughtered in this rash and ill-conducted enterprize.

In this unfortunate predicament, it happened luckily for the survivors that Nicuessa appeared with his ships. Being informed of what had happened to his rival, through his own rashness, he sent for him, and said that in such a case they ought to forget their disputes, remembering only that they were gentlemen and Spaniards. He offered at the same time to land with his men, to assist Hojeda in revenging the death of Cosa and the rest. Nicuessa accordingly landed with 400 men, which was more than sufficient to defeat the Indians, whose town was taken and burnt. By this victory the Spaniards acquired a vast number of slaves, and got so much booty that each shared seven thousand pieces of gold. Nicuessa and Hojeda now agreed to separate, that each might pursue the plan of discovery and settlement which was directed by their respective commissions.

Understanding that Nicuessa intended to steer for Veragua, Hojeda made all sail for the river of Darien; but having lost his old pilot, on whose experience he chiefly depended, he missed the river, and resolved to establish a settlement on the eastern promontory of the gulf of Uraba, which he did accordingly, calling his new town St Sebastian; because that saint is said to have been martyred by the arrows of the infidels, and was therefore thought a fit patron to defend him against the poisoned arrows of the Indians. He had scarcely fixed in this place when he found all the inhabitants of the country to be a race of barbarous savages, from whom he could only expect all the injury they could possibly do him and his colony. In this situation, he dispatched one of his ships under Enciso to Hispaniola, with orders to bring him as large a reinforcement of men as possible, and immediately set to work in constructing entrenchments to secure his remaining people against the natives. Provisions growing scarce, so that his people could not subsist, be found himself soon obliged to make excursions into the country in order to obtain a supply; but he was unsuccessful in this measure, and had the misfortune to lose many of his men by the arrows of the Indians, which were poisoned with the juice of a stinking tree which grows by the sea side. By these disasters, his new colony was speedily reduced to a very wretched situation; starved if they remained within their works, and sure to meet death if they ventured out into the country. While in this state of absolute despair, they were surprised one day by seeing a ship entering the port. This was commanded by Bernard de Talavera, no better than a pirate, who, flying from justice, had taken shelter in this place, to him unknown. Hojeda was in too great extremity to be nice in his inquiries into the character of Talavera, but readily bought his cargo, and treated him so well in other respects, that Talavera entered into his service. However serviceable this relief, it was but of short continuance, as all their provisions were soon consumed, and the savages were even more troublesome than before, if possible. As no succours appeared from Hispaniola, they were reduced to vast straits, and Hojeda at length determined upon going to St Domingo in order to procure supplies. Leaving Francis Pizarro to command the colony in his absence, he embarked in the vessel belonging to Talavera, but the voyage was unfortunate from its very commencement. Hojeda not only used too much severity to the crew, but behaved haughtily to Talavera, who laid him in irons; but a storm soon arose, and the crew knowing him to be an experienced seaman, set him at liberty, and it was chiefly through his skill that they were enabled to save their lives, by running the ship ashore on the coast of Cuba. Although it was only a short distance from thence to Hispaniola, Talavera durst not go there, and prevailed on Hojeda to venture a voyage of an hundred leagues in a canoe to Jamaica, which they performed in safety. Hojeda had some pretensions by his commission to the island of Jamiaca, and on hearing formerly that the admiral Don James Columbus had sent Don Juan de Esquibel to that island, he had threatened to cut off his head if ever he fell into his hands. He was now, however, under the necessity of applying to Esquibel for assistance, and was used by him with kindness. After a short stay in Jamaica, he went over to Hispaniola, where he learnt that Enciso had sailed to St Sebastian; and his own credit was now so low that he was hardly able to purchase food, and died shortly afterwards of want, though he deserved a better fate, being one of the bravest men that ever sailed from Spain to the West Indies. Talavera remained so long in Jamaica, that the admiral heard of his being there, and had him apprehended, tried, and executed for piracy.