Emergency dispatchers in Lancaster County were called at about 4:45 p.m. Monday about the crash in East Donegal Township.
Police said a car heading south on River Road crossed into the northbound lane and hit another vehicle head-on.
Authorities said the drivers, both residents of Conoy Township, were pronounced dead at the scene.
Lt. Stephen Englert of Susquehanna regional police said roads were wet but not icy at the time. The cause of the crash remains under investigation.