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Emergency services were called to Cairnmuir Rd near Bannockburn at 1.44am after a van hit a tree.
A police spokesperson said two people were airlifted to hospital with serious injuries.
One of the occupants was initially trapped in the vehicle.
St Johns spokeswoman Ngaire Jones said two people were airlifted to Dunedin Hospital, both with serious injuries
Another person was transported to Dunstan Hospital in Clyde with moderate injuries
A police spokewoman said there were four people in the van.
A tow truck removed the vehicle from the scene.