Police are investigating whether the victims of a fatal car crash in Melbourne's north on Saturday night were skylarking.

Five young men were killed and a girl seriously injured when their car hit a tree on Plenty Road at Mill Park in Melbourne's north about 2:00am AEDT.

Police believe the car was travelling at about 140 kilometres per hour when it hit the tree, tearing it from the ground, and splitting the car in two.

Assistant commissioner Tim Cartwright says he is frustrated by the tragedy.

"This is just crazy. How many times do we have to say to people speed kills?" he said.

"This isn't speed, this is lunacy.

"There's suggestions of earlier erratic driving. The witnesses we've got give us every indication this is just one person driving in a stupid manner that's resulted in this.

"There's at the moment no suggestions of drag racing, there's no oncoming traffic, two lane road, perfect conditions. What can you say? I'm just speechless really."

A 15-year-old girl, the lone survivor of the crash, was trapped in the wreckage with serious injuries for an hour and a half before she was cut free and taken to hospital. Her brother was killed in the accident.

Another pair of siblings, two brothers, were also killed.

The car was overloaded and police are investigating a report that a passenger may have been hanging out of a window earlier in the night.

Police are also trying to find out if the victims had been at a party.

Paramedic Ron McLeod, who has worked at crash scenes for 30 years, says the crash is the worst he has witnessed.

Mr McLeod has begged teenagers to take notice of this as an example the consequences of dangerous driving.

"We get a lot of heavy accidents along that stretch of road but as I've said, it's the worst," he said.

"It's very traumatising for the ambulance crews that worked on the patient.

"It's a horrific scene here this morning and young people should... Guys and girls just look what's happened here, there's a number of families that have lost loved ones and it's just a tragic scene."