The history of smallpox in Mexico is from Spain's conquest of the Aztec Empire in the early 16th century until the official declaration of the extinction of smallpox in 1951. Smallpox in Mexico has a history of five centuries. Smallpox was first introduced to Mexico by the Spanish. The colonists spread to central Mexico and may have become an important factor in the fall of Tenochtitlan, the capital of the Aztec Empire. 