The fleet set sail from Cadiz Spain on September 24, 1493. There were a total of 17 ships, Two were of the naos class (three masted) and 15 were the caravel design. The Nina from the first voyage and a ship named the Pinta, likely a replacement of the ship from the first voyage, were two of the caravels. Also a new ship was built in the Americas named Santa Cruz or India.

The expedition landed on November 3, 1493 on the island of Dominica. The voyage continued to several islands of the Lesser Antilles. Some of the islands included Montserrat, Antigua, Saint Martin, and Saint Croix. He also sighted and named the island chain of the Santa Úrsula y las Once Mil Vírgenes (the Virgin Islands), and named the islands of Virgen Gorda. He continued to the Greater Antilles, and landed on the island of San Juan Bautista, present day Puerto Rico, on November 19, 1493.

The second voyage, was designed to establish some colonization in the Americas. The number of ships was necessary for the more than 1200 colonist including their livestock. Additionally, more soldiers were in the group to help should there be resistance from the natives and to search for sources of gold.

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