State Highway 6 was closed for about four hours as a member of the serious crash investigation unit examined the scene.
Constable Doug Winter, of Cromwell, said a male passenger in the front seat of one car died in the crash.
The 23-year-old driver was treated by paramedics before being flown to Dunedin Hospital with "serious" injuries, a St John spokesman said. The man was later admitted to intensive care.
The occupants of a four-wheel-drive - the male driver and his pregnant wife, who sustained serious injuries - were transported to Dunedin Hospital by a second rescue helicopter. The pair, believed to be in their early 30s, were in a stable condition last night.
About 20 motorists gathered behind the police cordon at the scene to watch proceedings.
A woman in one vehicle, understood to have been one of the first people on the scene, was given oxygen and treated by St John ambulance staff for shock.
Sergeant Mike Williams, of Cromwell, said the dead man's details would not be released until next-of-kin had been contacted.
The injured had not yet been interviewed because they were in Dunedin Hospital receiving treatment, he said.
"There were no witnesses to the incident, other than the passengers in the vehicles."
SH6 was closed from 1pm to 5pm, with motorists advised at Tarras and Omarama.
