In 36 the Romans under Mark Antony (Antony, Mark) attacked Parthia, penetrating through Armenia into Media Atropatene. Phraates, however, defeated Antony, who retreated with heavy losses. In 34 Phraates' vassal king in Media made an alliance with Antony; but when Antony later withdrew, the Parthians reoccupied Media. A revolt soon broke out in Parthia, and Tiridates II of Armenia drove Phraates from the throne, forcing him to take refuge with the Śaka nomads. In 30, however, Phraates was able to regain power, and Tiridates fled to the Romans with the son of Phraates as a hostage.

The emperor Augustus made peace with Phraates and returned his son. Armenia and Osroëne were recognized as Roman dependencies. Augustus also sent Phraates an Italian concubine named Musa. On her advice, Phraates sent four of his sons to Rome, where they remained as hostages of Augustus. Phraates was later poisoned by Musa, who then ruled jointly with her son Phraates V.