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Police were called about 2.50pm to the crash, on the Te Anau-Mossburn highway (State Highway 94), between Block Christie Rds.
A police spokeswoman said three people had sustained serious injuries and a fourth moderate injuries. It was thought some other people had minor injuries.
Patients have now been airlifted to Dunedin Hospital.
Police remain at the scene and motorists are asked to avoid the area.