The accident happened just past midnight on Monday morning at 15th Street and Erie Avenue in the Tioga Nicetown section of the city.
The impact of the collision tossed one of the cars on its side.
Rescue workers had to cut open one of the cars to get to a 51-year-old man who was trapped in the wreckage.
He was taken to Temple University Hospital where he is being treated for a wide range of serious injuries.
Police are trying to determine what caused the accident.