The head-on crash occurred at about 9:15 p.m. Saturday on Highway 20 east of Clearlake Oaks, in the area of mile post marker 39.5, according to radio traffic and California Highway Patrol reports.
Vehicles involved were described as a silver SUV and a white sedan, with a third vehicle reported to be 30 feet down an embankment.
First responders reported the vehicles were blocking the roadway when they arrived.
There were a total of six patients, with two seriously injured, according to radio reports.
Firefighters and deputies were reported to be looking for additional crash victims in the creek but radio traffic did not indicate any were found.
Ground ambulances transported several of the patients, with two air ambulances requested to respond to Adventist Health Clear Lake Hospital to transport two crash victims to out-of-county trauma centers, scanner traffic said.
The air ambulances were reported to have flown the two most seriously injured patients to Santa Rosa Memorial Hospital.
Firefighters reported clearing the scene just after 11 p.m.
Additional information was not immediately available late Saturday night.
Email Elizabeth Larson at