For much of the day it was reported that four people had been injured, but in an update shortly before 8pm police confirmed two people had died at the scene.
The Otago Daily Times understands there are children among the injured.
Police were called to the scene, on State Highway 1 between the intersections with Titri and Bungards Rds, about 12.15pm.
After police initially reported "serious injuries", a Hato Hone St John spokesman said about 1.45pm that four people had been taken to Dunedin Hospital, three in a critical condition and one serious.
Earlier, St John said three ambulances and two helicopters had been sent to the scene.
A witness who asked not to be named said she felt "traumatised driving past" about 12.30pm before emergency services arrived.
"I didn't see it happen, but it looked horrific," she said.
"I don't know how it would have happened as it was right on the brow of the hill, so no one should have been considering passing."
A Fire and Emergency New Zealand spokesman said three appliances, from Milton, Waihola and Balclutha were responding.
The highway was closed for several hours but in an update shortly after 5pm, Waka Kotahi advised it had reopened.
During the closure, a reporter at the scene said traffic was being diverted down Titri Rd.
Police this evening said an inquiry was ongoing.
