Multiple fatalities were reported following the crash on Interstate 78 in Fredericksburg, Pennsylvania Emergency Management Agency spokesman Cory Angell said.
State police said more than 50 vehicles were involved in the crash, which happened around 9:45am (local time). The pileup left tractor-trailers, box trucks and cars tangled together across three lanes of traffic and into the snow-covered median about 120km northwest of Philadelphia.
Megan Manlove of Penn State Hershey Medical Centre said 10 patients had been brought in from the crash, three in critical condition, three with moderate to severe injuries and four with minor injuries.
Angell said drifting snow had been reported in the area and officials are investigating whether that may have had something to do with the crash.
"You could be driving down the interstate and all of a sudden conditions change because the winds are drifting the snow," he said.
Angell said drivers are urged to use caution because of blowing snow and extremely cold temperatures.