In 542, Roman Emperor Justinian was enjoying the rise of the Byzantine Empire that he helped to build with its new headquarters in Constantinople. The old western part with its center in Rome had been taken over by barbarians, vandals, and others. Through a series of military victories, Justinian's forces had been able to recapture much of Italy and had also been successful on other fronts. It was in the midst of these successes that Constantinople was ravaged by the first case of a black death pandemic. It reached Justinian's capital from Egypt, probably carried by rats in ships.

Symptoms of black death included bubonic swelling in the groin, armpits, or on the thighs on the 2nd day of infection. Some of the infected developed mental problems while others went into a deep coma. Death came quickly usually within a few days. When small black pustules appeared in the skin, the infected individual usually died within a day. Another symptom, vomiting blood, almost always led to death within a few hours. The physicians of that time tried a variety of cures but the results were always negative. In the sixth century there was no significant understanding of bacteria and their role in the spread of diseases, and nothing was yet known anywhere about genes and their critical influence in determining who survived and who did not.

Historians have estimated that close to half the population of Constantinople died from the plague during its four or five months of active infections. The number of soldiers left for Justinian's campaigns was completely inadequate so he had to step back from defending or further extending the historic frontiers.