The California Highway Patrol reported that the collision took place shortly before 11:30 a.m. near Robinson Rancheria in Nice.
A white pickup rolled over and hit two other vehicles, blocking the roadway.
CHP, Lake County Sheriff's deputies, Caltrans and Northshore Fire medics responded to the scene.
Three subjects, whose names were not immediately available, were reported injured, and two air ambulances came to the scene to transport them to the hospital.
The CHP reported the roadway was closed, with vehicles being diverted at the Reclamation Road cutoff.
Caltrans road signs were activated at the intersections of Highway 20 and Highway 53 and Highway 20 and Highway 29 to alert drivers to the closure.
The roadway reopened at 1:10 p.m., the CHP reported.
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