U.S. Route 222 Business (US 222 Bus.) is a 12.17-mile (19.59 km) business route of US 222 located in Reading, Pennsylvania. The southern terminus is at US 222 in Cumru Township. Its northern terminus is at US 222 in Ontelaunee Township. The route begins at the US 222 freeway and heads through the southwestern suburbs of Reading as Lancaster Avenue, intersecting Pennsylvania Route 724 (PA 724) in Shillington. US 222 Bus. continues into Reading on Lancaster Avenue and intersects the northern termini of PA 625 and PA 10 before reaching an interchange with the US 422 freeway. The business route crosses the Schuylkill River and becomes Bingaman Street. US 222 Bus. turns north on 5th Street and intersects US 422 Bus. in downtown Reading and the southern terminus of PA 61 to the north of downtown. The route interchanges with the PA 12 freeway and continues north through suburban Muhlenberg Township as 5th Street Highway. US 222 Bus. reaches Temple and continues northeast to its northern terminus as Allentown Pike. US 222 Bus. is the only auxiliary route of US 222 in Pennsylvania.

With the creation of the U.S. Highway System in 1926, the road between Reading and Lancaster was designated US 222 while the road between Reading and Allentown was part of US 22, which ran along what was designated the William Penn Highway in 1916 and PA 3 in 1924. In the late 1920s, US 222 briefly ran concurrent with PA 41 and PA 240 at different times. PA 42 originally ran north–south through Reading starting in 1927. By 1930, the concurrent state route designations were removed from US 222 and US 22. US 222 entered Reading along with PA 73 along Lancaster Avenue and Bingaman Street before turning north on 9th Street along with PA 83 to end at US 22 and US 422 at Penn Street. US 22 continued north on 9th Street out of Reading and continued along Kutztown Road through Temple toward Allentown. US 120 began at US 222 at Bingaman Street and headed north on 4th Street and Center Street out of Reading. In 1931, US 22 was moved to a more direct alignment between Harrisburg and Allentown, and US 222 was extended north along the former alignment between Reading and Allentown. US 222 was shifted to use Lancaster Avenue, Bingaman Street, and 5th Street and 5th Street Highway through the Reading area in the 1930s, running concurrent with US 122 through downtown Reading. The US 122 overlap was removed in 1963 and the PA 73 concurrency was removed by 1966. In 1975, US 222 was rerouted to bypass Reading on the West Shore Bypass and the Warren Street Bypass, with the former alignment through the city becoming US 222 Bus. In 1998, US 222 Bus. was extended north to its current terminus following the rerouting of US 222 to a new outer bypass of Reading. The business route was extended south to its current endpoint in 2004 with the completion of the US 222 freeway south of Reading to Mohnton.