A Cobram man, 25, underwent surgery after being critically injured in a two-car crash at Barnawartha on Saturday morning.
Ambulance Victoria said the man had a head injury and was flown to Royal Melbourne Hospital by air ambulance while another man with a chest injury was flown to Alfred Hospital in a serious condition.
The head-on collision occurred about 6.31am on Murray Valley Highway between Coyles Road and Mildrens Road.
The highway remained closed for about six hours after the incident.
Acting Sergeant Sarrah O'Keefe, of Wodonga, said the crash involved the Cobram man driving a white Mitsubishi Triton ute and a Tallangatta man, 28, in a maroon Toyota Surf.
"One vehicle has veered into the path of another, causing the head-on," she said.
"We're investigating whether or not fatigue, driver distraction, alcohol, drugs or speed were a factor."
Police have spoken to a number of witnesses.
EARLIER:Two car drivers have been airlifted to hospital after a head-on collision at Barnawartha on Saturday morning.
Wodonga police said the incident occurred about 6.30am on the Murray Valley Highway between Coyles Road and Mildrens Road.
Acting Sergeant Sarrah O'Keefe said the highway was expected to be closed in this area for several more hours while investigations continued.
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She said each car had a single male occupant and both were airlifted to hospital for treatment, one in a critical condition, the other stable.
Any witnesses to the collision should call Wodonga police on (02) 6049 2600 or Crime Stoppers on 1800 333 000.