One man has been killed, a teenager seriously injured, while a truck driver is also suspected to have died following a fiery crash in the state's south west.
A truck and a four-wheel-drive collided on the Glenelg Highway near the town of Tarrington about 6.05am on Tuesday.
The semi-trailer burst into flames.
Police have grave fears for the truck driver, whose remains they suspect to be in the wreckage.
It had been unclear earlier whether the driver was trapped in the charred wreckage, or had been thrown from the vehicle.
A 26-year-old South Australian man, who was driving the 4WD, died at the scene.
His male passenger, 17, and also from South Australia, had to be cut from the 4WD and has been flown to the Royal Melbourne Hospital with life-threatening injuries, where he remains in a critical condition.
A man is dead, a teen has critical injuries and a truck driver is presumed dead after a fiery smash near Hamilton. pic.twitter.com/wga3By8UjZ— 7 News Melbourne (@7NewsMelbourne) February 9, 2016
The fire was so fierce it took 11 fire crews nearly two hours to bring under control.
Emergency services have not yet been able to access the truck's cabin.
Hamilton police Inspector Nick Finnegan said it was an "horrific scene".
"At this stage one person is deceased, one is in a Melbourne hospital in critical condition and sadly we believe the driver of the truck is within the remains of the vehicle," he said.
"Investigators are working through that methodically."
Inspector Finnegan said the head-on collision sparked a fire in the truck that was carrying general cargo.
He said the blaze then "fed off" the prime mover's diesel fuel.
Assistant police commissioner Doug Fryer told 3AW Radio the semi trailer had been incinerated.
"It was a particularly nasty crash down there," he said.
"It could well be tragically a triple – we don't yet [know] – it will take some time."
The Glenelg Highway remains closed in both directions, and is not expected to reopen until at least noon on Wednesday.
"We will open the road as soon as possible as we understand the closure impacts on a lot of people, including school buses," Inspector Finnegan said.
"We will be keeping the local community informed."
The cause of the crash is not clear at this stage.
Anyone who saw the collision can contact Crime Stoppers on 1800 333 000.
With The Standard