The crash happened around 6:15 a.m. on the eastbound side of I-76.
Police say it was a head-on collision and two people were trapped and had to be rescued from their vehicles.
Police directed traffic off the Expressway at Belmont Avenue but eastbound has since reopened and westbound remains closed.
A medical helicopter was brought in to rush the victims to the hospital.
So far, there is no word on their condition.
Stay with 6abc.com as more information becomes available.