Because of its importance, Ctesiphon was a major military objective for the leaders of the Roman Empire in its eastern wars. The city was captured by Rome or by its successor state, the Byzantine Empire, five times in its history, three times in the second century alone. The emperor Trajan captured Ctesiphon in 116, but his successor, Hadrian, decided to willingly return Ctesiphon, in 117, as part of a peace settlement. The Roman general Avidius Cassius captured Ctesiphon during another Parthian war in 164, but abandoned it when peace was concluded. In 197, the emperor Septimius Severus sacked Ctesiphon and carried off thousands of its inhabitants, whom he sold into slavery.
Late in the third century, after the Parthians had been supplanted by the Sassanids, the city again became a source of conflict with Rome. In 283, emperor Carus sacked the city uncontested during a period of civil upheaval. In 295, emperor Galerius was defeated outside the city. However, he returned a year later with a vengeance and won a tremendous victory which ended in the fifth and final capture of the city by the Romans in 299. He returned it to the Persian king Narses in exchange for Armenia and western Mesopotamia. In c.325 and again in 410, the city, or the Greek colony directly across the river, was the site of church councils for the Church of the East.
Emperor Julian was killed following a battle outside of the city walls, in 363, during his war against Shapur II. Finally, in 627, the Byzantine Emperor Heraclius surrounded the city, the capital of the Sassanid Empire, leaving it after the Persians accepted his peace terms.