The accident closed the intersection of Percival Street and Hawkesbury Valley Way for more than four hours.

Emergency services were called to the intersection at about 7.15am after a black Volkswagen Golf and prime mover truck collided.

Police said the VW was turning right out of Percival Street when it was hit by a semi trailer travelling east on Hawkesbury Valley Way.

Officers on the scene confirmed conditions were foggy at the time of the incident, but could not confirm if the fog contributed to the crash.

The 25-year-old driver of the Volkswagen Golf and the 18-year-old rear passenger were both trapped inside the vehicle and had to be freed by rescue personnel from the NSW Fire Brigades and State Emergency Service.

Both men were taken to Hawkesbury Hospital before they were flown to Westmead Hospital with serious head injuries.

The 25-year-old man died around midday, five hours after the crash took place. The 18-year-old man remains in a critical condition at Westmead Intensive Care Unit.

The other passenger, a 20-year-old man, who was sitting in the front, was able to free himself from the vehicle and was treated for minor injuries at the nearby RAAF hospital.

The 48-year-old driver of the prime mover also escaped unscathed, but was taken to Hawkesbury Hospital for mandatory blood and urine tests.

With Hawkesbury Valley Way closed for forensic investigations, peak hour motorists were forced onto back roads, with Richmond bound traffic diverted onto Cornwallis Lane, and Windsor bound vehicles directed into a grid locked Racecourse Road.

South Windsor traffic was also reduced to a crawl as motorists chose to detour via Macquarie Street.

Investigations into the circumstances surrounding the fatal crash are continuing and a report will be prepared for the information of the Coroner.

Police are appealing for anyone who witnessed the crash to contact Windsor Police Station via Crime Stoppers on 1800 333 000.