Data suggest that HIV prevalence rates among Muslim populations may be increasing due to unprotected sexual intercourse and shared injection equipment, despite popular belief that adherence to religious injunctions has shielded Muslim populations from the HIV epidemic. HIV prevention programs targeting Muslim populations to date have often lacked a theoretical foundation and have neglected the important Islamic concept of jihad, or struggle. This article reviews the cultural and religious factors that may facilitate or reduce HIV risk in Muslim communities. The theory of reasoned action and a harm reduction approach are utilized to demonstrate how the important concept of jihad can be integrated with HIV prevention theory to develop HIV prevention approaches at individual and structural levels. The proposed approach to HIV prevention must be validated, refined, and evaluated for specific cultures and locales through field testing.