AbstractSmallpox, caused by the variola virus (VARV), is prominent in modern histories of the ancient Mediterranean world. The disease, or the diagnosis of it, has shaped estimations of the scale and significance of epidemics and pandemics, notably the 2nd-c. Antonine plague, and the burden of disease in large cities and regions densely populated in antiquity. Here we synthesize recent paleogenetic and evolutionary biological literature that casts significant doubt on the existence of a VARV that caused a disease we would recognize – clinically, ecologically, or epidemiologically – as smallpox in antiquity. On the basis of current data, it is time archaeologists and historians began to eradicate smallpox from their histories of the ancient world.