It happened during heavy rain around 11:50 p.m. Sunday on Interstate 81, about 10 miles northwest of Harrisburg.
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The bus trip originated in New York, abc27 News in Harrisburg reports.
The bus drove off the roadway, struck an embankment and rolled onto its right side before hitting the back of a car that was stopped in the right lane of traffic, according to a crash report.
The three passengers were declared dead at the scene, the police report said, and others suffered injuries that ranged from minor to severe.
Authorities say 45 to 50 people were on board the bus when it flipped.
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"This is considered a mass casualty incident," Trooper Megan Frazer said. "We do have eight ambulances that assisted with us, as well as lifeline (emergency response), just because of how many people were involved and the amount of injuries."
The identities of the owner and driver of the bus have not been released. Frazer said Monday morning that more details about the wreck might not be released until Tuesday.
(The Associated Press contributed to this report.)