Though Europeans had technological advantages over the Indigenous peoples they conquered in the Americas, their greatest weapon was disease. Crosby, making an observation that was groundbreaking at the time of publication, identifies European triumph as the result of ecological imperialism, one of the book’s themes. Prior to contact, diseases existed endemically rather than as epidemics, with some exceptions. Human migration, however, “is the chief cause of epidemics” (37) because populations that were isolated from illnesses will easily succumb to them when they invade their lands. The New World was ravaged by the diseases brought from Europe because they were unknown to Indigenous populations that had no natural immunity to them. The first 100 years after contact were particularly brutal:

The victims of disease were probably greatest in number in the heavily populated highlands of New Spain (Mexico) and Peru, but as a percentage of the resident population, were probably greatest in the hot, wet lowlands. By the 1580s disease, ably assisted by Spanish brutality, had killed off or driven away most of the peoples of the Antilles and the lowlands of New Spain, Peru, and the Caribbean littoral […] (38).