The Ontario Provincial Police have closed Hwy. 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 41-year-old man from LaSalle, was pronounced dead at the hospital, while the other has serious, but not life-threatening injuries.
Police anticipate the highway will be closed until 1 p.m. The Ministry of Transportation needs to inspect the road first.
The OPP ask anyone who witnessed the crash or has dash cam video of the crash are asked to call the Kingsville detachment.