The Plague of Justinian (CE 541–542, with recurrences until 750) is a pandemic that afflicts the Byzantine (Eastern Roman) Empire and especially its capital, Constantinople, as well as the Sasanian Empire and port cities around the entire Mediterranean Sea, as merchant ships harbor rats that carry fleas infected with plague.

Some historians believe the plague of Justinian was one of the deadliest pandemics in history, resulting in the deaths of an estimated twenty-five to one hundred million people during two centuries of recurrence, a death toll equivalent to as much as half of Europe's population at the time of the first outbreak.

The plague's social and cultural impact will be compared to that of the Black Death that devastates Eurasia in the fourteenth century, but research published in 2019 will argue that the plague's death toll and social effects have been exaggerated.

In 2013, researchers will confirm earlier speculation that the cause of the Plague of Justinian was Yersinia pestis, the same bacterium responsible for the Black Death (1347–1351).

The latter will be much shorter, but will still kill an estimated one-third to one-half of Europeans.

Ancient and modern Yersinia pestis strains closely related to the ancestor of the Justinian plague strain have been found in Tian Shan, a system of mountain ranges on the borders of Kyrgyzstan, Kazakhstan, and China, suggesting that the Justinian plague may have originated in or near that region.

The plague will return periodically in the sixth, seventh, and eighth centuries

The waves of disease have a major effect on the subsequent course of European history.

Modern historians will name his plague incident after Justinian I, who is emperor at the time of the initial outbreak.

Justinian himself contracts the disease, but survives.