The accident happened on the A90 Dundee to Aberdeen dual carriageway near Fordoun at about 4:10pm yesterday.
Grampian Police said a silver Vauxhall Astra and a black Saab estate had been involved in the collision.
Fire crews were called to help release four people from one of the cars, while a helicopter transferred one of the injured to Ninewells Hospital in Dundee.
Traffic was diverted on to the A92 road for several hours last night.
Officers said the two people who died had been passengers in the same vehicle but could not say which until their families had been informed.
It was not possible to say last night whether the injuries suffered by the two other casualties were life-threatening.
A police spokesman said: “Drivers travelling north are encouraged to use alternative routes wherever possible as the road is expected to be closed for several hours.
“Accident investigation officers are still at the scene and attempting to ascertain exactly how this incident came about.”
He added: “Any member of the public who may have witnessed the incident is encouraged to contact Grampian Police by telephoning the 101 non-emergency number.”