The crash happened on the A18 Mountain Road, in the vicinity of the Mountain Box, at about 07:50 GMT.
Police said the man was driving towards Ramsey in a white Citroen Berlingo when it was in collision with a blue Ford Transit coming the other way.
The Transit driver was taken to hospital but his injuries are not believed to be life-threatening.
Det Insp Mark Newey said the family of the driver who died have been informed.
The road was closed for several hours following the crash and witnesses are asked to contact police headquarters.
A 22-year-old man has died after the van he was driving was in collision with another van in the Isle of Man.