The 60-year-old was involved in a two-vehicle accident on the M74.
The accident, understood to have been involving a car and a van, happened between the Canderside and Hamilton junctions of the M74 at around 6.20 am.
The 60-year-old motorist was rushed to hospital by paramedics but died following the collision.
A section of the carriageway between junctions six and eight remains closed for accident investigation work and police are still at the scene.
One commuter, travelling from Stonehouse to Glasgow, said: "There are thousands of cars, all waiting for half an hour or so and then doing U-turns.
"Nothing is moving, it's absolute chaos.
"I've been stuck here for more than an hour.
"I tried going via East Kilbride but it's jammed there too, everything is stuck."
Police said local diversions have been put in place.
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