Ardashir attacks again towards the end of his reign, in 238–240, taking several cities in Syria and Mesopotamia, including Carrhae and Nisibis.

The struggle resumes and intensifies under Ardashir's successor Shapur I, who invades Mesopotamia.

His forces are defeated at a battle near Resaena in 243 and the Romans regains Carrhae and Nisibis.

Encouraged by these victories, Roman Emperor Gordian III advances down the Euphrates but is repelled near Ctesiphon at the Battle of Misiche in 244.

Gordian III is then killed, and successor Emperor Phillip the Arab hastily negotiates a peace settlement.