We evaluated the efficacy of a gender-specific intervention to reduce sexual risk behaviors by introducing female-initiated methods to urban women with severe mental illness. Seventy-nine women received 10 sessions of an HIV prevention intervention or a control intervention. The primary outcome was unprotected oral, anal, or vaginal intercourse, expressed using the Vaginal Episode Equivalent (VEE) score. Knowledge and use of the female condom were also assessed. Women in the HIV prevention intervention showed a three-fold reduction in the VEE score at the 3-month follow-up compared to the control group, but the difference was not significant. These women were significantly more likely to know about female condoms, have inserted one and used it with a sexual partner at the 3-month follow-up and to have inserted it at 6 months compared to controls. The female condom may be a useful addition, for a subset of women with SMI, to comprehensive HIV prevention programs.