A 30-year-old man from Polegate was airlifted to hospital with serious injuries after a crash on the A22 at Nutley.
He was driving a Rover 100 which was in collision with a Mercedes A160 being driven by a 49-year-old woman from Chiddingly.
The road was closed for four hours after the smash on the Horney Common Road, which took place at about 5pm on Wednesday (September 17).
Police were assisted by Highways Agency staff at the scene and began an investigation. They are now appealing for anyone who may have witnessed the collision.
Sergeant Dan Pitcher from the Sussex Road Policing Unit said, “We are particularly keen to speak with anyone who may have witnessed the driving of a white Seat Leon seen travelling south on the A22 between Nutley and the Lampool Roundabout at the time.
“Anyone with information is asked to contact us via email@example.com or by calling 101, quoting Operation Ambleside.”