Demographic and lifestyle information from 9690 black patients diagnosed with cancer or cardiovascular disease was collected in an ongoing case–control study in Johannesburg, South Africa. Compared to never smokers, the odds ratio (OR) for lung cancer among current smokers was 16.3 (95% confidence interval (CI), 9.6–27.6) for men and 6.4 (95% CI, 4.0–10.4) for women. The corresponding OR for other smoking-related cancers was 4.6 (95% CI, 3.7–5.7) among men and 1.9 (95% CI, 1.6–2.2) among women, and for cardiovascular disease, 3.4 (95% CI, 2.1–5.4) among men and 1.5 (95% CI, 1.1–2.1) among women. Risks were higher among smokers than former smokers, and all risk estimates increased with increasing levels of smoking duration and intensity. Non-electric domestic fuel was associated with approximately 60% increase in the risk of smoking-related cancer, but not cardiovascular disease. Risks for cancers of cervix, oesophagus, oral cavity/pharynx, stomach, larynx, pancreas and anogenital region, as well as squamous cell carcinoma of skin were all significantly higher among current than never-smokers, with ORs ranging from 1.5 for cervix (95% CI, 1.2–1.8) to 14.7 for larynx (95% CI, 7.2–30). The risks of tobacco-related disease reported here are similar to that currently observed in Western countries, even though cigarette consumption is relatively low in this population.