The crash happened across both eastbound lanes of Route 30 between Stony Battery Road and Prospect Road Mountville around 2:30 a.m.
The roadway remained closed for six hours.
Both men were alone in their vehicles, which are reported to have been an SUV and a minivan.
West Hempfield Township police are continuing to investigate.
The identities of the men have not been released.
Follow Daily Voice for updates.
Click here to follow Daily Voice Hampden-Silver Spring and receive free news updates.