The motorway was closed eastbound, between junctions 16 and 17 at Swindon, following the accident on Monday.
Wilts Police said a Mercedes sprinter van travelling westbound was involved in a collision with a Ford Focus.
The Mercedes bounced over the central reservation and hit a Nissan Micra on the eastbound carriageway. The Canadian driver was pronounced dead.
A female front-seat passenger in the Nissan was taken to the Great Western Hospital in Swindon with severe head injuries.
The driver of the Mercedes and his passenger, both from Wales, were also taken to the hospital. The Ford Focus driver was also treated for shock.
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