The 79-year-old day time talk show host made the announcement at the start of Tuesday morning's "Live with Regis and Kelly," which he has hosted for more than a quarter-century - previously with Kathy Lee Gifford. Regis will step down around the end of the summer.
Meanwhile, the talk is already turning to who may replace him. Potential contenders include Survivor host Jeff Probst, Ripa's husband Mark Consuelos, actor Neil Patrick Harris, fill in co-host Bryant Gumbel, and "American Idol" host Ryan Seacrest.
