This cross-sectional study presents baseline data from women (n = 641) in a community-based randomized trial in Pretoria, South Africa. Women were eligible if they reported recent alcohol or other drug (AOD) use and condomless sex. Latent class analyses were conducted separately for those who reported sex work and those who did not. Among those who reported sex work, a Risky Sex class (n = 72, 28%) and Low Sexual Risk class (n = 190, 73%) emerged. Those in the Risky Sex class were more likely to report that their last episode of sexual intercourse was with their boyfriend (vs. a client/other partner) compared with the Low Sexual Risk class (p < 0.001). Among participants who did not report sex work, a Drug-Using, Violence-Exposed, and Impaired Sex class (n = 53; 14%) and Risky Sex and Moderate Drinking class (n = 326; 86%) emerged. The findings suggest that interventions for women who engage in sex work should promote safer sexual behavior and empowerment with main partners. Women who use AODs, experience physical or sexual violence, and have impaired sex may be a key population at risk for HIV and should be considered for tailored behavioral interventions in conjunction with South Africa’s plan to disseminate HIV prevention methods to vulnerable women. Trial Registration: ClinicalTrials.gov registration NCT01497405.