Growing evidence suggests that drug and alcohol use are fueling the heterosexual transmission of HIV among African Americans. This study aims to examine the relative contribution of drug and alcohol use of male and female partners to risks of heterosexual transmission of HIV among 535 African American HIV serodiscordant couples (N = 1,070 participants) who participated in an HIV prevention trial. Associations found between use of drugs and alcohol by one or both partners and sexual risk indicators varied by type of substance and whether male or female partner or both partners reported use. The findings suggest multiple ways in which substance use of male and female partners may be contributing to the heterosexual transmission of HIV and other STDs among African Americans and underscore the need for HIV prevention strategies to address dyadic patterns of substance use that lead to sexual risks.