We aimed to assess prevalence and correlates of hazardous use of tobacco, alcohol and other drugs in a primary care population in Cape Town, South Africa. Stratified random sampling was used to select 14 of the 49 clinics in the public health sector in Cape Town, and every ‘nth’ patient, with those ages 18-25 oversampled (N = 2,618). Data were collected from December 2003 through 2004, using the World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test. Hazardous use of tobacco was most common, followed by alcohol and then other drugs. Hazardous tobacco use was associated with the 18-25 years age group, no religious involvement, high school completion, and higher stress. Hazardous alcohol use was associated with male gender, younger men, no religious involvement, employment, some high school education, and higher stress. Hazardous use of other drugs was associated with Colored (mixed) race (particularly among men), no religious involvement, employment, and stress. For all substances, women, particularly Black women, had the lowest rates of hazardous use. Although the study is cross-sectional, it does identify groups that may be at high risk of substance misuse and for whom intervention is urgent. Because prevalence of substance use is high in this population, routine screening should be introduced in primary care clinics.