Police were called at 4.30am following reports of an accident on Cheapside, close to McDonalds Restaurant.
A DAF truck had been involved in a crash with a white Scania van.
During the incident the driver of the DAF, a 47-year-old man, had become trapped between the two vehicles suffering serious injuries.
He was taken to Royal Preston Hospital where he remains in a serious condition.
The road was closed for four hours while accident investigators attended the scene.
Sgt Marc Glass, of Lancashire Police, said: “An investigation is underway following a serious road traffic collision in Lancaster.
“A man has been seriously injured and our thoughts are with the driver and his family at this difficult time.
“We are appealing to anyone who witnessed the collision and has not yet spoken with police to come forward.”
Anyone with information can contact police on 101 quoting log reference 0159 of October 27.