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It is thought that smallpox may have afflicted human populations for 10,000 years. From about 3000 years ago, on the mummified face of Pharaoh Ramses V of Egypt, are spots believed to have been caused by smallpox. Suspected cases have also been found in ancient China and India.

In 430 B.C., a plague hit Athens during the Peloponnesian War. It killed the great Athenian leader Pericles, among many others. It may have killed a third of the tightly clustered population. It had been Pericles' decision that the people of the countryside should move within the city walls for security against the Spartans and their allies. Although the move made the people defensible against human enemies, it proved especially hospitable to the plague, whether smallpox, one of the contenders, or some other virulent disease.

In 180, Marcus Aurelius, a conqueror better known as the Stoic Emperor of Rome, succumbed to some sort of disease, which may have been smallpox, brought into Rome by soldiers returning from Seleucia. Many soldiers also died from this, known as Galen's Plague. [See Ancient Plagues and Pandemics.] In about 250, a plague started in Africa and spread to Rome where it raged twenty years later.

The next well-documented plague happened under the mid-6th century Byzantine Emperor Justinian. As usual, we don't know what the plague disease was.

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