Police are appealing for witnesses following a collision on the A281 near Woodmancote on Monday evening.
Emergency services were called at about 6.50pm after a van and a car, which were both travelling in the same direction, collided near to the junction with Blackstone Lane, police say.
The van driver, a 28-year-old man from Haywards Heath, as well as his passenger, a 25-year-old man from Hassocks, suffered serious injuries and were taken to hospital.
The driver of the white Volkswagen Golf, a 36-year-old man from Hove, did not suffer any serious injuries, a spokesperson for Sussex Police confirmed.
Sergeant Carl Knapp said: “We would like anyone who was in the area and who saw what happened immediately before the collision to get in touch.
“Witnesses can email email@example.com or call 101 quoting Operation Creed.”
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