A section of the A59 Liverpool Road has been closed since 4.40am after a crash at the junction with Croston Road, near The Rufford Arms pub.
Police say the crash involved a HGV and a Ford Ka, with the Ka driver taken to hospital in a critical condition.
North West Ambulance Service said the casualty, a 48-year-old man from Manchester, has suffered 'major-trauma related injuries'.
The driver of the HGV was uninjured.
The A59 remains closed between Spark Lane and Sandy Lane and people are asked to avoid the area whilst police work at the scene.
A police spokesman said: "We were called at around 4.35am this morning (Wednesday, August 18) to the report of a serious collision involving a HGV and a Ford Ka on the A59 close to Croston Road, Tarleton.
"The driver of the Ka has been taken to Aintree Hospital.
"A diversion is in place whilst the road is closed and motorists are being asked to avoid the area."
Sgt Martin Wilcock, of Lancashire Constabulary's Serious Collision Investigation Unit, added: "This collision has left a man with some extremely serious injuries and my thoughts are with his loved ones at this time.
"I would appeal to anyone who witnessed the collision itself or who has any information to get in touch."
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