A man from Yeovil was among three people taken to hospital after a crash near Sherborne yesterday.
The road was closed while investigations took place and officers want to hear from anyone with dashcam footage.
Dorset Police were called to the A30 at Babylon Hill just before 4pm after a two-vehicle collision involving a grey Skoda Roomster and a silver Toyota HiAce panel van - near to the Marl Lane turn-off to Over Compton.
The driver of the Skoda, a local man, sustained serious injuries and his wife, who was travelling in the front of the car, sustained life-threatening injuries. Their family has been informed.
The driver of the Toyota van, a man from Yeovil, sustained minor injuries.
Police, fire crews and paramedics attended.
Sergeant Sarah Jones, from the traffic unit, said: "We are carrying out a full investigation to establish the circumstances of this collision.
"I am appealing to anyone who witnessed the collision to contact us.
"I would also urge any motorists who were travelling in the area at the time and have dashcams fitted to their vehicle to check their footage for anything relevant.
"Finally, I would like to thank motorists for their patience and understanding during the road closures.
"These have been absolutely necessary to allow the emergency services to respond and for a detailed examination of the scene to be carried out safely.
"Anyone with information is asked to contact Dorset Police via email at firstname.lastname@example.org or by calling 101, quoting incident number 21:259. Alternatively, contact Crimestoppers anonymously on 0800 555 111 or via Crimestoppers"