Melbourne residents will be able to head to regional Victoria from Friday following the easing of lengthy COVID restrictions.

Wangaratta Acting Senior Sergeant Tim Hart said there were concerns about a lack of recent driving, especially over long distances, and a sharp increase in vehicles on the road.

"We want people to enjoy the North East," he said.

"It's a wonderful place to visit.

"But we don't want to be bringing death messages to families as a result of post lockdown exuberance.

"We are expecting an influx of people from Melbourne and regional areas."

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Police will run an operation from tomorrow until Tuesday, and again next weekend, in a bid to prevent road trauma.

Officers will focus on high risk areas, including the high country and the Hume Freeway.

Police said there were at least four fatal collisions in regional Victoria in the five days after the recent easing of restrictions.

"All available personnel in North East Victoria, including highway patrol, uniform police and plain clothes police, will be tasked to traffic duties during those times," Acting Senior Sergeant Hart said.

"We'll be focusing on speed, impairment and fatigue.

"We fear we're facing a perfect storm with people not used to driving over long distances.

"It's probably never been more important to exercise caution, slow down and be aware of your surroundings."

Acting Senior Sergeant Hart said the Melbourne Cup long weekend had historically been bad for road trauma in regional areas.

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