The collision happened on stretch of Highway 63, about 70 kilometres south of the oilsands city of Fort McMurray.
RCMP say the two semis were travelling in opposite directions and crashed head-on.
One of the trucks was hauling diesel fuel and burst into flames.
Both drivers died.
About four or five other vehicles — another semi and some pickup trucks — hit the ditch to avoid the crash but no one else was injured.
Brad Grainger, deputy fire chief for the Rural Municipality of Wood Buffalo, said the road was "icy but clear" when the crash occurred Wednesday morning.
Firefighters had the blaze under control by noon.
"The fire crews are just letting it burn out, and then they're in the process of cleaning it up. We've got our dangerous goods unit down there as well."
Mounties closed the highway and were expecting to detour traffic for several hours.
Highway 63 is the main connector between Edmonton and the oilsands region.
It has been dubbed "Death Highway" because of its many fatalities over the years.
The provincial government is working to twin the highway to make it safer, but critics have said construction is not happening fast enough.
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