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Emergency services were alerted to a two-car crash on State Highway 8 near Lake Tekapo township about 9am.
In an update shortly before midday police confirmed one person had been killed and three people had been airlifted to Christchurch Hospital with moderate injuries.
The accident blocked the highway, which was still closed at 11.45am. Police said extensive delays were still expected. Motorists were asked to delay travel in the area.
Police said an alternate route would be Waimate to Kurow (southbound) on SH82 and SH83.
There was no word on the cause of the crash.
The crash brings the holiday weekend road toll to three after fatal crashes in the North Island yesterday evening and early today.