The California Highway Patrol was notified of a crash at 9:49 p.m. at 170th Street East and Avenue S-8.
Huntington Beach resident Emily Taylor, 49, was driving south on 170th when her Toyota Prius drifted into northbound lanes "for an unknown reason," according to the CHP.
The car collided with a Honda Accord driven northbound by Hesperia resident Alejandro Alvizures, 31.
Both drivers died at the scene.
"The investigation is still ongoing," the CHP reported. "Alcohol may have been a factor in this collision."
City News Service contributed to this report.