A smallpox epidemic swept through the Inca Empire, weakening it just in time for the Spanish conquistador Francisco Pizarro and his men and allies to conquer it. There is also strong evidence that the empire was already crumbling, its infrastructure damaged by overexpansion and its government by strife.
Incan Emperor Huayna Capac died of smallpox along with his heir just as the conquistadors made contact with the empire. Because he had two other sons, Atahualpa and Huascar, who aspired to the throne, his death triggered a civil war. Shortly after Atahualpa had his half-brother Huascar killed, Pizarro executed Atahualpa, then installed his own puppet king, a teenager named Manco Inca.
The Incas rose against Pizarro once more when Manco Inca's wife was stolen by Pizarro's brother. They were crushed by the heavily-armed Spaniards, and the increasing devastation of smallpox prevented further resistance.