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Emergency services responded to the two-vehicle crash at the corner of Thames St and Wear St at 7.42am today.
A St John spokesperson confirmed that three people were injured and one was flown to Dunedin Hospital in a serious condition.
The two other patients, one in a moderate condition and the other in a minor condition, were taken to Oamaru Hospital.
A police spokeswoman said it was believed one of the drivers had a medical event.