We assessed the relationship between stress, substance use and sexual risk behaviors in a primary care population in Cape Town, South Africa. A random sample of participants (and over-sampled 18-24-year-olds) from 14 of the 49 clinics in Cape Town’s public health sector using stratified random sampling (n = 2,618), was selected. We evaluated current hazardous drug and alcohol use and three domains of stressors (Personal Threats, Lacking Basic Needs, and Interpersonal Problems). Several personal threat stressors and an interpersonal problem stressor were related to sexual risk behaviors. With stressors included in the model, hazardous alcohol use, but not hazardous drug use, was related to higher rates of sexual risk behaviors. Our findings suggest a positive screening for hazardous alcohol use should alert providers about possible sexual risk behaviors and vice versa. Additionally, it is important to address a broad scope of social problems and incorporate stress and substance use in HIV prevention campaigns.