Troopers said the accident happened at 4:15 a.m. Saturday on Orange Avenue, near Perkins Road in Belle Isle.
A 30-year-old man was driving north on Orange Ave. when for unknown reasons, he swerved into the southbound lanes, troopers said.
Another car driven by a 35-year-old man was hit head on. Troopers said both men were killed in the crash.
Troopers were continuing their investigation and Orange Avenue remained closed through the morning.