Mithridates I of Parthia, taking advantage of Antiochus' western problems, had attacked from the east and seized the city of Herat in 167 BCE, disrupting the direct trade route to India and effectively splitting the Greek world in two.

Antiochus, recognizing the potential danger in the east but unwilling to give up control of Judea, had sent a commander named Lysias to deal with the Maccabees, while the King himself is to lead the main Seleucid army against the Parthians.

Setting out in 164 BCE on an expedition to the Arabian coast, he funds the city of Antioch on the Persian Gulf, where its mint is to serve the trade along the sea route between India and the district at the mouth of the great Mesopotamian rivers.

Near the end of the year, the fifty-one-year-old monarch of an illness at Tabae (or Gabae, probably present Isfahan) in Persis.

(Many believers see his death as a punishment for his attempt to loot the shrine of Nanaia in Elam, but this story seems to be baseless.