A silver Honda sedan was heading south on the highway at an unknown speed when the driver lost control and crossed over the asphalt center median at about 11:45 a.m., CHP Officer Steve Krul said.
The Honda went into oncoming traffic on the other side of the highway and was broadsided by a northbound Chevrolet Tahoe, he said.
A man, woman and an infant in the Honda were killed, and a toddler in the Honda was flown to Santa Rosa Memorial Hospital, Krul said.
The female driver of the Tahoe and a female juvenile passenger were flown to the Ukiah Valley Medical Center, and a male juvenile passenger was flown to Children's Hospital and Research Center in Oakland, Krul said.
The crash initially closed the highway in both directions, but one lane in each direction had reopened as of 3:15 p.m., Krul said.