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MELBOURNE - Four people, including two teenage girls, have been killed in a horrific road smash in Melbourne's south east.

The two girls, aged 13 and 15, and two men died after a collision between a Holden Statesman and a Holden Commodore at the intersection of Hallam and Ormond Roads in Hampton Park at 1.30am (AEST) on Sunday.

Authorities said the two teenage girls, travelling in the Commodore, died at the scene.

An 18-year-old man, a passenger in the Commodore, died on the way to hospital.

A man in his 20s was rushed to the Alfred Hospital but later died in the operating theatre.

Five other people, all aged in their teens or 20s, were injured in the crash, and rushed to different hospitals in Melbourne.

One woman in her 20s was trapped in one of the cars for an hour, and is now in a serious but stable condition, an Ambulance Victoria spokesman said.

Police are now investigating the fatal collision.

"As to the exact circumstances, we're not sure at the moment," a Victoria Police spokesman said.

"We're trying to piece it together."