Research has identified a wide range of health conditions related to alcohol and drug use in studies conducted primarily in developed countries and in populations with severe alcohol and drug problems. Little is known about medical conditions in those with less severe alcohol and drug use in developing countries. We used WHO AUDIT and ASSIST screeners to identify hazardous drinking or drug use in public health clinics in Cape Town, South Africa, and included questions about doctor-diagnosed medical conditions. Using logistic regression we examined the relationship of medical conditions to hazardous alcohol, drug and tobacco use. Those with hazardous substance use had higher prevalence of many health conditions including tuberculosis. Hepatitis B, migraine, chronic bronchitis, and liver cirrhosis. Optimal treatment for some medical conditions may include treatment of underlying hazardous substance use, particularly use of drugs other than alcohol. In these populations, access to substance use treatment is limited and even brief interventions or advice may be useful.