Objectives. To quantify the burden of disease attributable to smoking in South Africa for 2000. Design. The absolute difference between observed lung cancer death rate and the level in non-smokers, adjusted for occupational and indoor exposure to lung carcinogens, was used to estimate the proportion of lung cancer deaths attributable to smoking and the smoking impact ratio (SIR). The SIR was substituted for smoking prevalence in the attributable fraction formula for chronic obstructive pulmonary disease (COPD) and cancers to allow for the long lag between exposure and outcome. Assuming a shorter lag between exposure and disease, the current prevalence of smoking was used to estimate the population-attributable fractions (PAF) for the other outcomes. Relative risks (RR) from the American Cancer Society cancer prevention study (CPS-II) were used to calculate PAF. Setting. South Africa. Outcome measures. Deaths and disability-adjusted life years (DALYs) due to lung and other cancers, COPD, cardiovascular conditions, respiratory tuberculosis, and other respiratory and medical conditions. Results. Smoking caused between 41632 and 46 656 deaths in South Africa, accounting for 8.0 - 9.0% of deaths and 3.7 - 4.3% of DALYs in 2000. Smoking ranked third (after unsafe sex/ sexually transmitted disease and high blood pressure) in terms of mortality among 17 risk factors evaluated. Three times as many males as females died from smoking. Lung cancer had the largest attributable fraction due to smoking. However, cardiovascular diseases accounted for the largest proportion of deaths attributed to smoking. Conclusion. Cigarette smoking accounts for a large burden of preventable disease in South Africa. While the government has taken bold legislative action to discourage tobacco use since 1994, it still remains a major public health priority.