The Main Line of the Pennsylvania Railroad was a rail line in the U.S. state of Pennsylvania, connecting Philadelphia with Pittsburgh via Harrisburg. The rail line was split into two rail lines and now all of its right of way is now a cross-state corridor, composed of Amtrak's Philadelphia to Harrisburg Main Line (includes SEPTA's Paoli/Thorndale Line service) and the Norfolk Southern Railway's Pittsburgh Line.
The eastern part of the PRR's main line (east of Lancaster) was built by the Commonwealth of Pennsylvania as part of the Main Line of Public Works, a hybrid railroad and canal corridor across the state. The system consisted of the Philadelphia and Columbia Railroad from Philadelphia west to Columbia on the Susquehanna River, the Eastern Division Canal from Columbia to Duncan's Island, the Juniata Division Canal from Duncan's Island to Hollidaysburg, the Allegheny Portage Railroad from Hollidaysburg to Johnstown, and the Western Division Canal from Johnstown to the terminus in Pittsburgh. The Philadelphia and Columbia Railroad had one inclined plane at each end; the Allegheny Portage Railroad had ten. The parts that were later included in the PRR main line opened from Philadelphia to Malvern (the end of the West Chester Railroad) in 1832 and Malvern to Lancaster in 1834. A short piece of the Allegheny Portage Railroad in East Taylor Township and Conemaugh Township, including the Portage Viaduct over the Little Conemaugh River, later became part of the PRR main line; it was opened in 1834.