Update, 5.55pm: Police have confirmed two people have died as a result of the collision.
Emergency services were called to the scene after receiving reports that two cars had collided about 2.45pm.
Police said the driver of a north bound Commodore crossed over to the wrong side of the road and collided with a car travelling south.
Two passengers in the Commodore died at the scene. They are yet to be formally identified.
A young child who was also in the Commodore has been flown to hospital with life threatening injuries and the male driver has been taken to hospital by road ambulance.
The female driver of the other vehicle involved also suffered injuries and is going to hospital.
Update, 4.40pm: Police have confirmed a person has died as the result of the collision.
Emergency services are still on scene and the road remains closed.
Breaking news: 4.00pm: Emergency services are responding to a major collision on the Goulburn Valley Hwy near Gillespies Rd.
The highway is closed in both directions and is under Victoria Police control. It will re-open when it is safe to do so.
Drivers have been asked to consider Kattamate-Shepparton Main Rd to get around the closure.
More to come.