Early in 66 the tribune Gaius Manilius proposed that Pompey should assume supreme command of the war against Mithridates and Tigranes. He should take control from the provincial governors in Asia Minor, have the power to appoint legates himself and the authority to make war and peace and to conclude treaties on his own discretion. The law, the Lex Manilia, was approved by the Senate and the People and Pompey officially took command of the war in the east.

On the approach of Pompey, Mithridates retreated into the centre of his kingdom trying to stretch and cut off the Roman supply lines but this strategy did not work (Pompey excelled at logistics). Eventually Pompey cornered and defeated the king at the river Lycus. As Tigranes II of Armenia, his son-in-law, refused to receive him into his dominions (Greater Armenia), Mithridates fled to Colchis, and hence made his way to his own dominions in the Cimmerian Bosporus. Pompey marched against Tigranes, whose kingdom and authority were now severely weakened. Tigranes then sued for peace and met with Pompey to plead a cessation of hostilities. The Armenian Kingdom became an allied client state of Rome. From Armenia, Pompey marched north against the Caucasian tribes and kingdoms who still supported Mithridates.