Blacks in the USA, including black men who have sex with men (MSM), tend to have stronger religious and spiritual affiliations compared with other racial/ethnic populations. HIV and STD incidence rates continue to rise among Black MSM. Using data from the CDC Brothers y Hermanos (ByHS) project, this study examined correlations between high-risk behavior, e.g., substance use and high-risk sexual behavior (e.g., condom use history, unprotected sexual intercourse, HIV infection status, and STD infection status) religiosity, spirituality, age, among Black MSM (N = 1141). This exploratory study examined whether religiosity and spirituality were associated with high-risk behavior and high-risk sexual behavior among Black MSM. Religiosity and spirituality indices were compiled from the ByHS data. The religiosity index was significantly associated with HIV infection and use of cocaine, crack, and poppers as well as marginally associated with ecstasy use. Spirituality was significantly associated with HIV infection status, STD infection status, alcohol use, and crack use. Given these relationships, current and future HIV prevention models targeting Black MSM should consider the potential importance of the roles of religiosity and spirituality in the lives of Black MSM to increase the efficacy of risk reduction interventions.