Diodotus II—accused, it is thought, of treason to Hellenism through his alliance with the nomads—loses his throne around 230 or 223 BCE to a usurper, his brother-in-law Euthydemus I, founder of the Greco-Bactrian Euthydemid dynasty (Polybius, 11.34, 2).

Arcases' successor Artabanus I (sometimes known as Arsaces II, who reigned from about 211 BCE to 191 BCE, continues the work of consolidation of the  Parthian realm.

Being already solidly established in Parthia and Hyrcania, Artabanus tries to extend his possessions toward Media, but events in the neighboring Greco-Bactrian kingdom work against him.

Antiochus having entered upon the eastward campaign (212-205) for which he will gain renown, now attacks Artabanus.

The Parthians may in fact be hostile to the local Greek populations: during the initial phase of the war, they massacre all the Greek inhabitants of the city of Syrinx in Hyrcania.

Antiochus takes Syrinx and Hecatompylos, the Arsacid capital (the present location of which is uncertain), then crosses the mountains separating that province from Parthia, which he occupies.

Artabanus flees and takes refuge with the friendly Apasiacae, as had his father, Arsaces I.

The conflict between the Seleucids and Parthia, however, is ended by a compromise, just as it had been at the time of the invasion of Seleucus II.

A much more important struggle against the Bactrian kingdom of Euthydemus awaits Antiochus.

Preferred to make peace with Artabanus, he accords him the title of king in exchange for recognition of his fealty, and obliges the Parthian to send troops to reinforce the Syrian army.

This safeguards the rear of the Seleucid king, but the Macedonians have definitively lost the two provinces held by Artabanus.

Antiochus meets strong resistance at the frontier by the Bactrian cavalry.

Euthydemus, failing in his attempt to defend the line of the Arius (Harirud) River, had fallen back to his capital, Bactra (probably Balkh in northern Afghanistan), where he withstands a two-year siege.

Finally, Antiochus concludes a peace by which Euthydemus is to keep his kingdom while acknowledging Seleucid overlordship.

Antiochus returns westward via the Iranian provinces of Arachosia, Drangiana, and Carmania.

Arriving in Persis in 205, Antiochus receives tribute of five hundred talents of silver from the citizens of Gerrha, a mercantile state on the east coast of the Persian Gulf.

Having established a magnificent system of vassal states in the East, Antiochus now adopts the ancient Achaemenid title of “great king,” and the Greeks, comparing him to Alexander the Great, surname him also “the Great.” Antiochus' long campaign has produced meager results, however.

He has recognized the independence of two kingdoms, that of the Parthians and that of Euthydemus, which had been no more than satrapies.

The struggle must have weakened these two, but after receiving legalization of their status, the two states proceed to the reestablishment of their material and military resources.