Objectives. To make quantitative estimates of the burden of disease attributable to alcohol use by sex and age group in South Africa in 2000. Design. The analysis follows the World Health Organization comparative risk assessment (CRA) methodology. Population-attributable fractions (PAFs) calculated from modelled prevalence estimates and relative risks based on the global review were applied to the burden of disease estimates from the revised South African National Burden of Disease study for 2000. The alcohol-attributable fractions for injuries were directly determined from blood alcohol concentrations (BAC > 0.05 g/100 ml) at the time of injury. Monte Carlo simulation-modelling techniques were used to quantify uncertainty in the estimates. Setting. South Africa. Subjects. Adults = 15 years. Outcome measures. Deaths and disability-adjusted life years (DALYs) from ischaemic heart disease, stroke, hypertensive disease, diabetes, certain cancers, liver cirrhosis, epilepsy, alcohol use disorder, depression and intentional and unintentional injuries as well as burden from fetal alcohol syndrome (FAS) and low birth weight. Results. Alcohol harm accounted for an estimated 7.1% (95% uncertainty interval 6.6 - 7.5%) of all deaths and 7.0% (95% uncertainty interval 6.6 - 7.4%) of total DALYs in 2000. Injuries and cardiovascular incidents ranked first and second in terms of attributable deaths. Top rankings for overall attributable burden were interpersonal violence (39.0%), neuropsychiatric conditions (18.4%) and road traffic injuries (14.3%). Interpersonal violence accounted for 42.8% of the injury DALYs attributed to alcohol in males and 25.9% in females. In terms of alcohol-attributable disability, alcohol use disorders ranked first (44.6%), interpersonal violence second (23.2%), and FAS third (18.1%). Conclusions. Particular attention needs to be given to preventing and reducing the burden of alcohol-related homicide and violence, alcohol-related road traffic accidents, alcohol use disorders, and FAS. Multilevel interventions are required to target high-risk drinkers, in addition to creating awareness in the general population of the problems associated with alcohol abuse.