It happened after 6 am Saturday on Turner Island Road near Palazzo Road.
The California Highway Patrol says a 26-year-old woman was driving north on Turner Island when she ran off the right side of the road.
The woman corrected, but ended up in the southbound lane and hit a silver Toyota head-on.
Officials say a 39-year-old man from the Toyota was flown to a nearby hospital with major injuries.
The woman was also taken with major injuries.
Law enforcement don't believe drugs or alcohol were a factor.