During the first two centuries of the Christian era, Iran was Parthian territory. The Parthian Empire was internally unstable and, moreover, came into regular conflict with Rome, usually as a result of aggressive Roman provocation. Periods of war alternated with periods of armed peace. The Romans tried to profit from the differences between, on the one hand, the Parthian rulers and, on the other, the Parthian and Iranian aristocracy. This necessitated a complex and subtle diplomacy. Rome was ceaselessly trying to expand, and some Roman emperors, deliberately emulating Alexander the Great, aimed specifically at enlarging the empire in the East. The emperor Trajan, most notably, established the provinces of Armenia, Assyria, and Mesopotamia after having beaten the Parthians. His successor Hadrian, however, gave up these newly gained territories in exchange for a peace treaty, and the Euphrates again became the border. Later, during the 2nd century, the Parthians in their turn invaded the Roman Empire. They were driven back, but peace did not return; there was a decennia-long situation of conflict with varying tactical chances. At the same time, the Parthians were fighting the Sakas and Kushan on the eastern borders of their territory. It was this warfare on two fronts and internal unrest that brought about the decline of the Parthian Empire. At the end of the 2nd century, the emperor Septimius Severus managed to conquer a large area beyond the Euphrates that, as the province of Mesopotamia, would be part of the Roman Empire until 336 AD, with only some minor interruptions.
In around 230 AD, the role of the Parthians was taken over by the New Persian Empire of the Sassanids. The Sassanid Empire began as a rebellion against Parthian authority led by a Parthian vassal and developed into a deliberate attempt to restore the former Achaemenid Empire. This, as has been noted, had also been the aim of the Parthian kings, but they had never been able to realize their ideal. The Sassanids were more energetic. Their often obdurate attitude toward the minorities in their territories was inspired by a return to a strict Zoroastrianism. The Greeks, who under the tolerant and syncretistically minded Parthians had known flourishing communities, were among the victims of these new policies. A more aggressive position toward the outside world also fits this image. For the Romans, the fall of the Parthian Empire meant a worsening of the situation: unlike the Parthians, the Sassanids did manage to establish a strong centralized state. Right from the beginning, they were a serious threat to the eastern borders of the Roman Empire. For centuries the Sassanids stood their ground and inflicted defeats on Romans as well as Hephthalites. The New Persian Empire lasted until 642 AD.