The Sea to Sky Highway, closed in both directions after a head-on collision, reopened to single lane alternating traffic Saturday afternoon.
Police say a car heading north with two people inside drifted across the centre line and struck an oncoming southbound car also carrying two people.
One person from each car suffered serious injuries. They were both taken to Vancouver General Hospital by helicopter.
The other two occupants with less serious injuries were taken by ambulance to the Whistler Health Care Center.
Those travelling on Highway 99 are warned to expect lengthy delays until the highway is fully reopened.
There is no indication that alcohol or drugs are involved in the collision and police continue to investigate in an effort to determine the cause of this crash.