Persons with severe mental illness (SMI) comprise a growing proportion of the HIV-infected population, likely fueled by high rates of substance abuse. This article documents the rate of HIV infection among persons dually diagnosed with SMI and substance use disorders (SUDs) and reviews empirical studies examining the association between substance abuse and sexual risk behavior. It then discusses potential mechanisms through which substance abuse might relate to sexual risk behavior, including additive/synergistic effects of SMI and SUD. The evidence suggests that dually diagnosed persons are at high risk for HIV, yet little is known about how substance abuse contributes to sexual risk behavior. Directions for future research and recommendations for clinical practice are outlined.