The crash happened just after midnight Friday on the northbound lanes of Route 202 between Mill Lane and Swedesford Road in East Whiteland Township.
According to police, a 2015 GMC Sierra being operated by 42-year-old Matthew Deangelis, was traveling southbound in the northbound lanes and hit a 2022 Volkswagen Taos head-on.
Deangelis was pronounced dead at the scene.
Rescuers say the driver of the Volkswagen was transported to the hospital in critical condition. As for the passengers, one had to be extricated and a second was able to walk away.
The conditions of those victims have not been released.
"It's sad. It's a tragedy," said Fire Chief Gregory Lewis of East Whiteland Township Fire and Emergency Services.
Lewis said the wreck was so bad that crews had to free multiple people.
"We had a driver trapped in one vehicle and a driver and a rear passenger trapped in the second vehicle. Our rescue crews split and began extractions in both vehicles," he said.
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The crash temporarily closed the northbound lanes.
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Investigators have not said whether Deangelis was under the influence of any substances at the time of the crash.
The circumstances of the crash remain under investigation.