BACKGROUND: Substance misuse is a global public health problem. In addition to social and economic concerns, consumption of tobacco and alcohol is associated with susceptibility to cardiovascular, respiratory, and infectious diseases, cancers, and risk of transition to substance use disorders. African data suggest regional differences in the prevalence and patterns of substance use, but a number of key questions remain. This cross-sectional population-based study of middle-aged adults aims to examine prevalence and socio-demographic correlates of substance use in four sub-Saharan African countries, in rural and urban settings. METHODS: Participants aged between 40 and 60 years were recruited from six research centres as part of the Africa Wits-INDEPTH partnership for Genomic Research study. Data on patterns of tobacco and alcohol consumption was captured, and the latter further assessed using the CAGE (cut-annoyed-guilty-eye) questionnaire. RESULTS: Data from 10,703 participants suggested that more men (68.4%) than women (33.3%) were current substance users. The prevalence of current smoking was significantly higher in men than in women (34.5% vs 2.1%, p < 0.001). Smokeless tobacco was used more by women than men (14.4% vs 5.3%, p < 0.001). Current smoking was associated with alcohol consumption in men, and smoking cessation in men was associated with being a former drinker, having higher socio-economic status, and if married or cohabiting. Current alcohol consumption was higher in men, compared to women (60.3% vs 29.3%), and highest in men from Soweto (70.8%) and women from Nanoro (59.8%). The overall prevalence of problematic alcohol consumption among men was 18.9%, and women 7.3%. Men were significantly more likely to develop problematic drinking patterns, and this was more common in those who were divorced or widowed, and in current smokers. CONCLUSIONS: Regional variation in the patterns and prevalence of substance use was observed across study sites, and in rural and urban settings. The high levels of substance use recorded in this study are of concern due to the increased risk of associated morbidities. Further longitudinal data will be valuable in determining trends in substance misuse in Africa.