The accident happened last night on the A77 near the village of Ballantrae.
Police said it involved a black Ford Fiesta which left the northbound carriageway and collided with an Audi.
The 18-year male driver of the Ford was taken to Glasgow's Southern General Hospital suffering from serious leg and arm injuries. He is said to be serious but stable.
Two 19 year old passengers from the Ford, the 32 year old driver of the Audi and his 60 year old male passenger were all taken by ambulance to Ayr Hospital for treatment.
Medical staff describe their condition as stable.
Constable George McAsh of Irvine Road Policing Unit said: "I would like to speak to anyone who was in the vicinity of the A77 near to Ballantrae at the time of the crash.
"I would also be very keen to speak to members of the public who may have seen the black Ford Fiesta being driven on the A77 earlier in the evening, just prior to the crash occurring."
Anyone with information is asked to contact Constable McAsh at Irvine Road Policing Unit on 101.