Wangaratta Highway Patrol members are appealing for witnesses following a crash in Porepunkah.
Investigators have been told a blue Mercedes Benz station wagon was travelling along Great Alpine Road about 6pm on Saturday night.
The car left the road and crashed into a tree.
The driver of the car, a 44-year-old South Melbourne man, and his passenger, a 47-year-old Quarry Hill man, suffered serious injuries and were taken to hospital.
Police are continuing to investigate the circumstances surrounding the incident and wish to speak to anyone who saw the Mercedes prior to the crash.
Anyone with information or with dashcam footage is urged to contact Crime Stoppers on 1800 333 000 or submit a confidential report at www.crimestoppersvic.com.au.