The Ontario Provincial Police has reopened Highway 3 between Cameron Side Road and County Road 27 outside of Cottam.
Police say there was a two-vehicle crash just after midnight Tuesday at that intersection, and the driver of each vehicle was taken to the hospital.
A pickup truck collided with an SUV, and then caught fire.
One driver, a 39-year-old man from LaSalle, was pronounced dead at the hospital, while the other, a 24-year-old woman, has serious, but not life-threatening injuries.
Highway 3 between Cameron Side Road and County Road 27 was closed for over 12 hours to allow police to investigate and the Ontario Ministry of Transportation to inspect the road. It reopened shortly before 1 p.m. on Tuesday.
The OPP ask anyone who witnessed the crash or has dash cam video of the crash to call the Kingsville detachment.