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.

The force has urged bargain hunters to refuse to buy illicit food, alcohol, fashion, medicines and beauty goods, which could contain hidden dangers.
Make-up laced with paint stripper was another product highlighted at a summit being held in Edinburgh on counterfeit goods and criminal gangs.
The event includes speakers from Interpol and US Homeland Security.
Scottish Justice Secretary Kenny MacAskill said: "Buying counterfeit goods might be seen as a victimless way to get presents for family and friends on the cheap, but many of these items will have a long back story of criminality, often involving violence.
"However, the problem doesn't just lie with fake bags, perfume or alcohol.
"There is a serious global problem in counterfeit medicines, machinery and engine parts which can be seriously damaging to people's health and potentially deadly."
Mandy Haeburn-Little, director of summit organiser the Scottish Business Resilience Centre, said: "Everyone loves a bargain. But people need to stop to think about the true cost of fake goods. Can you be confident that those cheap cigarettes, perfumes and alcohol are actually safe?
"However, it goes much deeper as those products are likely to have supported child labour or human trafficking or used to fund serious organised crime.
"Illicit trade also hurts businesses in Scotland very hard. People choosing bargains at markets, car boot sales or on the internet impacts hugely on retailers and manufacturers - less genuine goods being sold closes businesses and puts people out of work."

The 25-year-old former Ipswich Town youngster has made more than 230 appearances for the U's, but was hampered by injury last season.
Contract options have also been taken up for defenders Lewis Kinsella, Kane Vincent-Young and winger Drey Wright.
Wright, 22, has featured 101 times for the U's, while Kinsella, also 22, joined from Aston Villa last summer.
Vincent-Young, 21, featured 23 times last season for the U's.
A 22-year-old man has died after the van he was driving was in collision with another van in the Isle of Man.
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Dog skin boots and perfume containing urine were among a range of fake goods seized by Police Scotland.
[NEXT_CONCEPT]
Colchester United defender Tom Eastman has signed a new two-year contract with the League Two side.