The Guards said General Hossein Hamedani was killed on Thursday night and that he had "played an important role ... reinforcing the front of Islamic resistance against the terrorists".
Iran is the main regional ally of Syrian President Bashar al-Assad, and has provided military and economic support during Syria's four-year-old civil war.
Iran denies having any military forces in Syria, but says it has offered "military advice" to Assad's forces in their fight against "terrorist groups".
Hamedani was a veteran of the 1980-88 Iran-Iraq war and was made deputy chief commander of the elite forces in 2005.
In the biggest deployment of Iranian forces yet, sources told Reuters last week that hundreds of troops had arrived since late September to take part in a major ground offensive planned in west and northwest Syria.
Iranian lawmaker Esmail Kosari said Hamedani helped coordination between Syrian armed forces and the voluntary forces in their fight against the IS militia.
"For years, Hamedani played a very important role in Syria as an adviser ... he played an important role in preventing the fall of Damascus. Then he returned home at the end of his assignment," Kosari told the semi-official Tasnim news agency.
"He returned to Syria for a few days because of his deep knowledge about the area ... and he was martyred in Syria."
Assad's longtime ally, Russia launched its air campaign in September, saying it would also target IS. But its planes have also hit other rebel groups opposed to Assad, including groups backed by Washington.
The United States and its allies have been waging a year-long air campaign against IS in Syria, while pushing to diplomatically edge Assad from power.
Washington has ruled out military cooperation with Russia in Syria, accusing Moscow of pursuing a "tragically flawed" strategy that would force it to limit military talks to basic pilot safety.
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