Emergency services responded to the crash about 10:30am on Saturday at Broken Head Road in Suffolk Park, just south of Byron Bay in northern NSW.
Police said the driver of one of the vehicles, believed to be a woman aged in her 50s, died at the scene.
The driver of a second vehicle - a man believed to be aged in his 60s - was also found dead.
A woman in her 60s, who was the passenger in the second vehicle, was treated by NSW Ambulance paramedics and airlifted to Gold Coast University Hospital in a critical condition.
The collision appeared to have been a head-on between the first two vehicles, a NSW Ambulance spokesperson said.
Two other people - believed to have been occupants of a third vehicle which rear-ended the others following the initial collision - were treated for minor injuries and transported by road to Tweed Hospital.
Police have established a crime scene and are investigating what caused the crash.
Broken Head Road was expected to remain closed for a number of hours between Beech Drive and Broken Head Reserve Road, with diversions in place.
People are urged to avoid the area, but anyone with information or dashcam footage of the incident is asked to contact police.
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