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The Persians invaded Armenia, Syria and the Roman territories in Mesopotamia (Iraq) several times in the course of the many wars between the Romans and the Persians over these territories. The Romans also carried out invasions of Persia during these wars. During one of these invasions the Persians captured a Roman Emperor, Valerian. The many wars with Persia were one of the factors which weakened the Roman Empire in its later days. In the end the Romans gave up part of Armenia to achieve peace.

In 114-115 the Roman emperor Trajan conquered Armenia and Mesopotamia (Iraq), taking these regions from the Parthian Empire (the third of the four pre-Islamic Persian empires). His successor Hadrian gave these conquered territories back to the Persians because he deemed them indefensible and because he wanted peace. Under the reign of Lucius Verus, co-emperor with Marcus Aurelius, there was the Roman-Parthian War of 161-166. The Parthians defeated the Romans in Armenia. The Romans retook Armenia, invaded Mesopotamia and sacked Ctesiphon, the Persian capital, but had to withdraw due to an epidemic. In 165-97 the emperor Septimius Severus seized northern Mesopotamia and sacked Ctesiphon. Caracalla fought a successful campaign against the Parthians, but when he was assassinated his successor was defeated. This was the last Roman-Parthian war. The Parthian Empire was succeeded by the Sassanid Empire, the last of the four pre-Islamic Persian empires.

In 230 The First Sassanid, emperor, Ardashir, raided Mesopotamia and Syria and demanded that these territories be given to him. The Roman emperor Alexander Severus pushed him back in 232. Ardashir attacked again in 238-240 and captured several cities in Mesopotamia and Syria. His successor, Shapur I invaded Mesopotamia, killed its king and defeated the Romans in a battle in 243. He was defeated in 244 and the emperor Giordan III advanced on Ctesiphon but was defeated near this city and was killed. His successor, Phillip the Arab made a peace treaty. However, soon after this, in 253, Shapur I invaded Armenia, defeated the Romans and sacked the major city of Antioch in Syria. In 258 he defeated the emperor Valerian and captured him. He pushed into what is now Turkey but was defeated by the Romans. He was forced to surrender Antioch and Armenia and to withdraw from all Roman territories by Odaenathus of Palmyra, an ally of the Romans in Syria.

In 283 the emperor Carus invaded Persia and sacked Ctesiphon. He could not extend his conquest because he died. During the reign of Diocletian the Persians invaded Armenia, but his co-emperor, Galerius, defeated them in 298 and captured the Persian emperor's treasury and harem. The Romans pushed further into northern Mesopotamia. In 299 Shapur II conducted unsuccessful campaigns. He failed in a siege of a city and two cites he captured were retaken by the Romans. He seized a city in 359. The emperor Julian counterattacked and won a battle at Ctesiphon, but failed to capture the Persian capital. He was killed in a skirmish while he was withdrawing from Persia. His successor, Jovian, made peace and surrendered Roman territory in Mesopotamia east of the river Tigris. Shapur II conquered Armenia. In 384 or 387 a peace treaty between Theodosius I and Shapur III divided Armenia into two states. This peace lasted because both empires suffered attacks on their frontiers.

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