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Police said they were alerted to the two-vehicle crash on State Highway 85 at the intersection with Loop Rd about 3.23pm.
A St John spokesperson said the surviving patients had been assessed, with one suffering serious injuries and another moderate. Both have been transported to Dunedin Hospital by helicopter.
Emergency services worked to extract another person from the wreckage but it appears they died at the scene.
Thee ambulances attended the crash.
Earlier, Fire and Emergency services southern shift manager Mau Barbara said two trucks were present, with another two on the way.
Crews from Omakau, Alexandra and Ranfurly had been called.
The highway reopened as of 9.20pm.
- additional reporting NZ Herald