In 2006, Santorum sought re-election to a third Senate term and ran unopposed in the Republican primaries.[84] His seat was considered among the most vulnerable for Republicans and was a prime target of the Democratic Party in the 2006 elections. His opponent was Democratic State Treasurer Bob Casey, Jr., the son of popular former governor Robert Casey, Sr.. Casey was well known for his opposition to abortion, negating one of Santorum's key issues.[85]
For most of the campaign, Santorum trailed Casey by 15 points or more in polls.[86] According to the Philadelphia Inquirer, Santorum "encouraged everyone in state politics to help the Green Party earn a spot on the November ballot", with the result that 14 Santorum supporters funded a Green Party petition drive for Carl Romanelli, a railroad industry consultant.[87][88] Romanelli came up 9,000 signatures short of the total required for ballot access, further hurting Santorum's prospects, as there were no other candidates to siphon away votes from Casey.[89]
Santorum was mired in a residence controversy after stating that he spent only "maybe a month a year" at his Pennsylvania home.[90] Critics pointed out that Santorum himself had once denounced his former opponent U.S. Representative Doug Walgren for living away from his House district.[91] Critics also complained that Pennsylvania taxpayers were paying 80% of the tuition for five of Santorum's children to attend an online "cyber school"--a benefit available only to Pennsylvania residents.[92] After the Penn Hills school district challenged the Santorum's residency and billed Santorum $73,000, he withdrew the children from the cyber school, and suggested they were being used as political pawns by his opponents.[92]
Santorum aimed a television ad suggesting that Casey's supporters had been under investigation for various crimes. The negative ad backfired, as the The Scranton Times-Tribune found that all but a few of Casey's contributors donated when he was running for other offices, and none were investigated for anything.[93] In fact, two of the persons cited in Santorum's campaign ad actually gave contributions to him in 2006, and one died in 2004.[94] Santorum's campaign countered that those donations were not kept, and had been donated to educational institutions.[95] Santorum faced controversy for statements against "radical feminism", which he claimed had made it "socially affirming to work outside the home" at the expense of child care.
Toward the end of his campaign, Santorum shifted his theme to the threat of radical Islam.[73][96] In October 2006 he gave a "Gathering Storm" speech, invoking British Prime Minister Winston Churchill's description of Europe prior to World War II.[73][96] As evidence that Islamists were waging a more than 300-year old crusade against the Western world, Santorum pointed to September 11, 1683, the date of the Battle of Vienna.[97] Casey responded, "No one believes terrorists are going to be more likely to attack us, because I defeat Rick Santorum."[98] Noting that he had been "even more hawkish" during this time period than President Bush, Santorum later said, "Maybe that wasn’t the smartest political strategy, spending the last few months running purely on national security".[96]
A heated debate between the candidates occurred on October 11, 2006.[99] Bill Toland of the Pittsburgh Post-Gazette described both candidates' performances during the debate as "unstatesmanlike".[99]
In the November 7, 2006 election, Santorum lost by over 700,000 votes, receiving 41% of the vote to Casey's 59%, the largest margin of defeat for an incumbent senator since 1980[100] and the largest losing margin for an incumbent Republican senator ever.[101]
On April 12, 2007, political action committee America's Foundation, Highmark and a former Highmark vice president were fined by the Federal Election Committee for providing Santorum with corporate money for campaign fundraising events.[102] The problem had been reported by Highmark, which uncovered the matter during an internal review.