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A police spokeswoman said emergency services were called to the crash at the intersection of Fruitlands-Roxburgh Rd and Roxburgh-East Rd, near Roxburgh, at 6.45pm.
Three people suffered moderate injuries and a rescue helicopter was called due to the remote location on State Highway 8.
The police spokeswoman said one of the vehicles was carrying fruit, which scattered across the road.
Road users were asked to follow emergency services for alternate route and to allow extra travel time.