On April 10, 2010, Karger held a press conference at the Southern Republican Leadership Conference (SRLC) in New Orleans, to announce that he was "seriously considering becoming a candidate for President of the United States in 2012 as an Independent Republican." He attended the SRLC with other potential candidates for the Republican Presidential ticket such as Sarah Palin, Ron Paul, Rick Santorum, Newt Gingrich and Gary Johnson. This was the day after GOP Presidential candidate Romney announced forming his 2012 exploratory committee; Karger declared himself the "Anti-Romney" candidate, and later stated that he "plans to run a campaign specifically designed to throw a wrench into Romney's run." Since making his announcement, Karger has been to Iowa and New Hampshire several times, holding town hall meetings, talking to voters, as well as meeting with political, LGBTQ, AIDS organization leaders and the media.
On July 18, 2010, Karger announced he had formed an exploratory committee for the United States presidential election of 2012.
In November 2010, Karger aired a weeklong ad campaign in Iowa which was described as the first television commercial of the 2012 presidential race. Steve Scheffler, an Iowa delegate to the national Republican National Committee, has said Karger is part of the radical homosexual community. His campaign has made use of the slogan "Fred Who?"
Karger has stated that his "budget is five to six million, which is, of course, a congressional race budget", and has also indicated that his "goal in running" is "to inspire the next generation through his candidacy." Karger's candidacy has been described as a long shot, with one interviewer indicating that "[t]he question on the minds of many" is "does he think he has a snowball’s chance? The answer to that is, yes and no."
Karger officially announced his candidacy on March 23, 2011.
On March 31, 2011, Karger won the Saint Anselm College Republicans Presidential Straw Poll in Manchester, New Hampshire, receiving 25% of the vote. He defeated favored candidate Mitt Romney by five votes: "Karger placed first in the St. Anselm College Republican Straw Poll in Manchester, New Hampshire with 79 votes out of a total 322 ballots. Romney was close behind with 74 votes, while Donald Trump came in a distant third with 26 votes, just edging out former Gov. Tim Pawlenty (R-Minn.) and U.S. Rep. Ron Paul (R-Texas). The poll was of students, faculty and staff of St. Anslem."
In late April 2011, Karger attended the national convention of the Log Cabin Republicans in Dallas and declared to the conservative gay organization that he wants his presidential campaign to "open up" the Republican Party and send a message to young people and gay people: "You can do anything you want to do." Karger told OC Weekly that gay Republicans need to "stand up and be proud in a tough atmosphere."
In June 2011, he filed a formal complaint with Massachusetts authorities, accusing fellow Republican nomination candidate Mitt Romney of having registered and voted in Massachusetts when his primary residence was in another state.
He has been endorsed by The Real World: Washington D.C. cast member Mike Manning.
On July 13, 2011, Karger called fellow GOP presidential candidate Michele Bachmann a "liar, hypocrite, and bigot" when she refused to comment on allegations Bachmann's husband was using conversion therapy in his clinic to attempt to cure gays of homosexuality and saying that homosexuality was a choice.