After the fall of the Inca Empire many aspects of Inca culture were systematically destroyed, including their sophisticated farming system, known as the vertical archipelago model of agriculture. Spanish colonial officials used the Inca mita corvée labor system for colonial aims, sometimes brutally. One member of each family was forced to work in the gold and silver mines, the foremost of which was the titanic silver mine at Potosí. When a family member died, which would usually happen within a year or two, the family was required to send a replacement.

The effects of smallpox on the Inca empire were even more devastating. Beginning in Colombia, smallpox spread rapidly before the Spanish invaders first arrived in the empire. The spread was probably aided by the efficient Inca road system. Smallpox was only the first epidemic. Other diseases, including a probable Typhus outbreak in 1546, influenza and smallpox together in 1558, smallpox again in 1589, diphtheria in 1614, and measles in 1618, all ravaged the Inca people.

There would be periodic attempts by indigenous leaders to expel the Spanish colonists and re-create the Inca Empire until the late 18th century.