Police believe a motorbike lost control before smashing into a police car near Bairnsdale in Victoria's east, killing both on board.

The motorbike rider and pillion passenger crashed into the police car on the Great Alpine Road, at Ensay at about midday on Saturday.

The 47-year-old man and 42-year-old women died at the scene.

Acting Assistant Commissioner Dean McWhirter from Victoria Police said the car and the motorbike were going in opposite directions.

"A police vehicle was travelling in a southerly direction and a motorcycle with a pillion passenger was travelling in a northerly direction," he said.

"Whilst we're not clear in terms of the exact cause of the accident, it appears the motorcycle has lost control and collided with the police vehicle.

"Unfortunately both the rider and the pillion passenger ... died as a result of being involved in the accident."

The police officer in the car was not injured.

In a horror start to the long weekend in Victoria, two other people were also killed in separate road-related incidents.

A man believed to be in his 20s died when he was hit by a truck at Wandong, north of Melbourne.

Police said he was walking along the Hume Freeway just after 4:00am when he was struck.

In another incident, a man was killed when he was thrown from his vehicle after it crashed through a fence at Cranbourne South, in Melbourne's outer south-east.