When the series first began, General Hospital was set in an unnamed city or town somewhere in the United States of America. Between 1964 and 1966, Queen's Point, the setting of the short-lived soap opera, The Young Marrieds, was considered to be a suburb of that same unnamed city, part of a plan to feature regular crossovers between the two shows which never materialized due to the cancellation of Marrieds. It was not until 1977 that the General Hospital setting was finally established as the fictional city of Port Charles, New York.
The early history of Port Charles is not extensively covered onscreen. Character dialogue indicates that the city once had an extensive milling industry, for which catacombs were built to divert water. The catacombs have played a role in numerous storylines; years later, in a 1985 plot, they were extended under the city's Asian Quarter.
A storyline broadcast in 1985 revealed that, at some time in Port Charles' history, a large ghetto area known as the Asian Quarter was built to house the city's Asian population. Racial discrimination in the city has been a point of tension many times; minority residents were reportedly denied housing and bank loans in the mid-20th century, and one of Port Charles' first African-American council members, the character Bradley Ward II, faced racist opposition from his white counterparts in the 1970s (he was later murdered). Homosexuality became a topic after Bobbie Spencer's adopted son Lucas Jones was the victim of a gay basher. Other plots have dealt with issues such as the planned construction of a polluting incinerator near the city's ethnic neighborhoods.
Port Charles is portrayed as a fairly large city, approximately the size of Rochester or Buffalo, located in Western New York somewhere on the shores of Lake Ontario between the Buffalo–Niagara Falls and Syracuse areas. In 1993, the producers of General Hospital filmed several exterior locations in and around the Western New York area, including Letchworth State Park and the village of Perry. The skyline of downtown Rochester stands in for aerial shots of Port Charles.
Within the fictional universe of General Hospital, the city of Port Charles coexists closely with the real cities of Rochester, Buffalo, and Niagara Falls. Events in the series in which characters travel to nearby cities indicate that Port Charles is located relatively close to all of these locations. Port Charles is depicted as a separate metropolitan area; its description and location relative to Buffalo and Syracuse suggest a thinly disguised version of Rochester itself. Separate from but proximate to both Rochester and Buffalo, and located on a body of water (as "Port" would indicate), the most likely location for Port Charles would be on Lake Ontario north of Batavia, lending credence to the theory that Port Charles represents Rochester. The city's ZIP code is 16543. According to the U.S. Postal Service Directory this specific postal code does not actually exist, however the zip prefix 165 is designated for Erie, Pennsylvania. Digital displays on phones seen on screen show a "716" area code prefix, which is the area code for the Buffalo-Niagara area and the western end of New York State. The area code for Rochester was changed to "585" in 2002, but was "716" from 1947 to 2001.
Several episodes broadcast in September 2013 made reference to a water shuttle connecting Port Charles directly with Toronto. Such a ferry service was at one time contemplated connecting Toronto and Rochester across Lake Ontario: it ran for a short period in 2004 and 2005 before being abandoned. On several occasions it has been implied (but never openly stated) that the opposite shore across from Port Charles Harbour is located in Canada.