The first encounters between Nahuas and Spaniards from 1519 to 1521 resulted in widespread deaths in the indigenous communities of central Mexico. Although the first recorded disease epidemic is often acknowledged as a factor in the loss of rule to the invaders, Moteuczoma receives much of the blame. Historians contend that Moteuczoma’s cowardice facilitated the defeat of his people. Instead, this article argues that descriptions of the pain and fright that afflicted Moteuczoma and his people in Book XII of the Florentine Codex are references to long-standing cultural concepts of illness. This article uses colonial and modern ethnographic sources to illuminate enduring Mesoamerican concepts of health and sickness. The chaos and loss of life connected to the first epidemic in 1520 contributed significantly to the fall of Tenochtitlan. This article reveals how Nahuas remembered and understood the startling arrival of the Spaniards and the first terrifying disease epidemic during the invasion.