The collision involved a white Mini Cooper and a grey Toyota Verso, and happened around 1.50am on Sunday (April 30) on the westbound A259 at Colworth.
A 25-year-old man from Littlehampton was taken to hospital with potentially life-threatening injuries.
Investigating officers are keen to speak to anyone who saw what happened, or who may have seen either vehicle travelling in the area beforehand.
Anyone with information or relevant dashcam footage is asked to contact Sussex Police on online or by calling 101 quoting Operation Milston.
