After years of media speculation about his sexuality, Pierce came out in 2007 and later confirmed through his publicist that he and television writer, director and producer Brian Hargrove were a couple. When accepting his Tony Award for Curtains, Pierce thanked "my partner, Brian, because it's 24 years of listening to your damn notes — that's why I'm up here tonight."They married in California on October 24, 2008, just days before Proposition 8 was adopted as law, banning same-sex marriages in the state. On May 28, 2009, while a guest on The View, he publicly announced his marriage to Hargrove and expressed his anger over the approval of Proposition 8. Pierce and Hargrove divide their time between New York and Los Angeles.
He and Frasier co-star John Mahoney are godparents to Frasier co-star Jane Leeves' son, Finn. Pierce has spent years working with the Alzheimer's Association on behalf of Americans with Alzheimer's disease. He has appeared in Washington D.C. to testify in support of expanding funding for treatment, and he has publicly campaigned for the (ultimately successful) National Alzheimer's Project Act. He told MSNBC in 2011, "it is up to us, to all of us, to the American people and to their representatives about whether we face the challenges and make all the effort necessary or if we ignore it and just let this sort of tidal wave crash over us." Pierce has spent years working with the Alzheimer's Association on behalf of Americans with Alzheimer's disease.