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A police spokeswoman said officers were called at 10.01am to a collision between two cars at the intersection of Longbush South Rd and Rimu Rd, just east of Invercargill.
At 11.25am police said one person remained trapped in one of the cars and was in a critical condition, but all passengers were taken to Southland Hospital by 12.30pm.
Another patient had a head injury.
St John spokesman Gerard Campbell said ambulance officers had treated three patients, one of whom was critically injured, while the other two had serious and moderate injuries.
Three ambulances and a St John manager were called to the crash.
The police spokeswoman said the cars were reported to be upside down and at least one of the vehicles was reported to be on fire.
A man living nearby said he had seen "flames coming out of the front of one of the cars" and emergency services had been working to free a person trapped underneath one of the vehicles.
That car was upside down in a ditch from which fire crews were drawing water, but they appeared to have extinguished the blaze, he said.
A Fire and Emergency New Zealand spokesman said crews from Invercargill had been sent to assist with freeing the people who were trapped in the vehicles.