Wofford's campaign was hurt from the outset by his strong connection with President Bill Clinton's failed healthcare reform proposals; Wofford had made working toward universal healthcare a crucial issue in his prior campaign and was one of the executive's strongest allies on the issue. After this failure, however, the senator ran a relatively passive campaign. He instead attempted to focus attention on his challenger, an arch-conservative who did not attempt to moderate his views after the primary election. The polarizing Santorum took strong positions against abortion, gay rights, and affirmative action, and he even clashed with some of the traditional fixtures of the state's moderate Republican establishment. Early in the campaign and with little statewide name recognition, Santorum made a critical error by attacking Social Security, and Wofford appeared to be in relatively safe position. However, Santorum ran an effective grassroots campaign and specifically targeted many union Democrats who had reservations about the liberal social values advocated by many of their party's leaders.
In the closing weeks of the campaign, Santorum was greatly helped by strong Republican enthusiasm because of anger over Clinton's failed initiatives. He solidified his status by running a series of positive ads that attempted to define his character strengths and to contrast with Wofford's negative commercials. Santorum eventually received a close victory by performing well (and nearly winning) his home in the suburban Pittsburgh region and through particularly low turnout in Democratic strongholds, such as Philadelphia, Scranton, and Pittsburgh.