Emergency services were called to the Great Alpine Road near Ensay about midday Saturday after the motorbike and police car collided.

Ambulance Victoria spokesman John Mullen said paramedics arrived to find one person dead and attempted unsuccessfully to revive a second person.

Acting Assistant Commissioner Dean McWhirter said the motorcycle, carrying a man, 47, and woman, 42, had been travelling in the opposite direction to the police car.

"There was a police vehicle travelling south and there was a motorcycle with a rider and pillion passenger travelling north," he said.

"It appears that the motorcyclist may have lost control prior to the collision and then collided with a police vehicle.

"They were on a recreational ride and they were with two other couples but the other couples weren't close by and didn't actually witness, or weren't involved in, the collision. They were about five or 10 minutes behind."

A Victoria Police spokeswoman said the male officer who was driving the police car was not injured.

The popular tourist road is closed between Bruthen and Ensay.

Four people have been killed on Victorian roads on the first day of the long weekend, after two men, both aged in their 20s, were killed in separate crashes on Saturday morning.

One man was killed in Cranbourne South when he ploughed through a fence and was thrown from his car.

A second man was killed when he was hit by a truck as he walked along the Hume Freeway in Wandong