A 28-year-old Meadow Heights man was driving a Ford Festiva when it struck the rear of a Mitsubishi four-wheel drive just before a Campbellfield railway crossing at about 6.30am.

He was rushed to the Royal Melbourne Hospital where he died at about 1.30pm.

His passenger, a 26-year-old Meadow Heights woman, was treated at the hospital with serious injuries.

The driver of the Mitsubishi,  a 52-year-old man from Coolaroo, was uninjured.

The second man died when he lost control of his truck and it flipped in the state's southwest at about 8am.

Police believe the truck veered off Portland-Nelson Road, Portland and rolled, landing on its side.

The man is yet to be formally identified.

Police will prepare reports for the coroner.

The deaths take the provisional road toll up to 72, four more than the same time last year.

Anyone who saw the maroon Festiva before it crashed on Barry Road is urged to contact Crime Stoppers on 1800 333 000.