The Northern Highway is closed in both directions between Argyle and Tooborac following a fatal crash near Tooborac this afternoon.
Emergency services responded to reports a semi-trailer truck and a car had collided on the Northern Highway just before midday.
The truck driver was taken to hospital with non-life-threatening injuries.
The driver of the ute, who is yet to be formally identified, died at the scene.
The exact cause of the crash is being investigated.
The highway, both north and southbound, will be closed for some time.
Emergency services are diverting traffic at Heathcote-Nagambie Road and Seymour-Tooborac Road.
Motorists planning to travel in the area this afternoon should allow extra time for the significant detours that include the Hume Freeway, Goulburn Valley Freeway, Bendigo-Murchison Road or the Midland Highway.
The closure is under the direction of police and the road will only re-open when investigations are complete.
Anyone who witnessed the collision, has dashcam/CCTV footage or information is urged to call Crime Stoppers on 1800 333 000 or via crimestoppersvic.com.au/report-a-crime.
Real-time traffic conditions are available at traffic.vicroads.vic.gov.au.