She met Bob Guccione in 1965 and they remained together, although they did not marry until 1988. In his publishing company her title was President/Chief Operating Officer of General Media Communications, Inc. She founded the magazines Viva (1973), Omni (1978), and Longevity (1989). She also wrote two non-fiction books, Woman of Tomorrow (1986) and Longevity: The Science of Staying Young (1992). She was plaintiff in the U.S. Supreme Court case of Keeton v. Hustler Magazine, Inc..
After her diagnosis with breast cancer, Keeton treated herself with hydrazine sulfate, after reading about it in Penthouse, one of her own publications. She claimed that she had ridden or shrunken almost all of the tumors and extended her life by several years, after being given a dire initial prognosis of only six weeks to live by her doctors.