The collision has left two drivers in a serious but stable condition at the John Radcliffe.
It happened at around 7.55pm on Sunday and involved a silver Vauxhall Insignia travelling from Oxford to Swindon and a silver VW Golf going the other way on the A420.
They collided at the junction with the B4508 near Watchfield and Shrivenham which resulted in serious injuries to the drivers of both vehicles.
Two passengers in the Golf suffered less serious injuries, all four remain in the John Radcliffe Hospital.
Investigating officer PC Duncan Vale of the Joint Operations Unit for Roads Policing based at Bicester, said: “This collision happened in the early evening on what is usually a busy stretch of the A420.
“I am appealing for anybody who may have seen the collision, or either of the vehicles described leading up to the collision, to please make contact with police"