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Honduras was originally inhabited by indigenous tribes, the most powerful of which were the Mayans. The western-central part of Honduras was inhabited by the Lencas. These autonomous groups had their conflicts but maintained their commercial relationships with each other and with other populations as distant as Panama and Mexico.

On July 30, 1502, Christopher Columbus first saw Honduran soil and he claimed the territory in the name of his sovereigns, Ferdinand of Aragon and Isabella of Castile. He named the area "Honduras" (meaning "depths") for the deep water off the coast.

In 1523 the first expeditionary forces arrived under the command of Gil Gonzales de Avila, who hoped to rule the new territory. In 1524, Cristobal de Olid arrived with the same intent on behalf of Hernan Cortes. Olid founded the colony Triunfo de la Cruz and tried to establish an independent government. When Cortes learned of this, he decided to reestablish his own authority by sending a new expedition, headed by Francisco de las Casas. Olid, who managed to capture his rivals, was betrayed by his men and assassinated. Cortes then traveled to Honduras to firmly establish his government in the city of Trujillo before returning to Mexico in 1526. Honduras formed part of the colonial era Captaincy General of Guatemala. The cities of Comayagua and Tegucigalpa developed as early mining centers.

By October 1537, the Lenca chief, Lempira, a warrior of great renown, had managed to unify more than two hundred native tribes in order to offer an organized resistance against penetration by the Spanish conquerors. After a long battle, Governor Montejo gained the Valley of Comayagua, established Comayagua city in another location, and vanquished the indigenous peoples in Tenampua, Guaxeregui, and Ojuera.