The most horrific crash in the horror period from 8pm on Friday claimed the lives of two men and a woman after the Commodore sedan in which they were travelling collided with a truck at Burrumbeet near Ballarat just after midnight on Saturday.

Road Policing Assistant Commissioner Doug Fryer said all six deaths could have been avoided, labelling fatigue, distraction, speed and impairment as factors in the tragedies. Those killed were aged from 23 to 82.

Mr Fryer called on Victorians to work together to stop the "carnage" on the roads. "We are now at 90 lives lost versus 76 last year," he said.

"If we all don't work together to address the carnage on our roads, we'll see an annual lives lost toll of over 300 this year. And we haven't seen that number since 2008."

The tragic toll across the state included;

* Three dead and one in a critical condition after the Burrumbeet crash,

* The death of a 23-year-old man in Hopetoun after his car crashed into a tree shortly after 8pm Friday,

* A crash at Tuerong on the Mornington Peninsula which claimed the life of a male driver and seriously injured a passenger. The death will not be added to the official road toll as it occurred on a private property.

* The death of a 58-year-old man in Myrtleford on Saturday morning after his car crashed into a tree,

* A motorcyclist in his 30s was left in a critical condition after crashing into a tree at Toongabbie in Gippsland,

Mr Fryer said it was too early to confirm, but there was some indication that alcohol was involved in two of the fatalities.

However, he said there were no drug or alcohol involved in the Burrumbeet crash which claimed the lives of an 81-year-old Maryborough man, an 82-year-old Beaufort man, and a 72-year-old Castlemaine woman. A 62-year-old woman from Beaufort is in a stable but critical condition at the Alfred Hospital.

Mr Fryer said the vehicle was attempting to cross the Western Highway when a B-double truck, travelling at 100 km/h "t-boned it".

"The car pulled in front and the truck …went straight through it," he said.

"A devastating scene. We have spoken to the truck driver, he is quite traumatised from it. He said he saw the car, and he thought the car saw him, it slowed down but then rolled through that intersection in his way. He was in a B-double truck and unable to stop."

The truck driver was not injured in the crash.

Mr Fryer would not confirm if there was any "alcohol involved" in the accident which saw a 23-year-old man die at Hopetoun. However, he confirmed the man had recently left a hotel.

Mr Fryer said it was too early to say but there could be medical issues that had contributed to the death of the 58-year-old man in Myrtleford.

He said the spate of accidents could not be blamed on the weather. "It hasn't been raining," he said.

Burrumbeet has been the scene of a series of fatal and serious accidents in recent years, a number involving trucks. Two young men and two other passengers were critically injured when a car ran off the road and into a tree in 2011. In 2012, a man was killed 3km west of Burrumbeet in a head-on collision between a car and a truck.

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Victoria's Roads and Road Safety minister Luke Donnellan said far too many people had been killed on the state's roads this year. "These numbers represent real people who will be missed by their families, friends and colleagues. A single life lost is one too many," he said.