BACKGROUND: Despite increasing obesity in South African adults, data on the prevalence and determinants of body mass index (BMI) from rural communities, home to a significant proportion of the population, are scarce. OBJECTIVES: To investigate overall and sex-specific determinants of BMI in a rural adult South African population undergoing rapid social and epidemiological transitions. METHODS: Baseline cross-sectional demographic, socioeconomic, anthropometric, clinical and behavioural data were collected between 2015 and 2016 from 1388 individuals aged 40-60 years and resident in the Agincourt sub-district of Mpumalanga province, a setting typical of rural northeast South Africa. A Health and Socio-Demographic Surveillance System (HDSS) underpins the sub-district and contributes to the Africa Wits-INDEPTH partnership for Genomic Studies (AWI-Gen). Linear regression was used to investigate univariate associations between log-transformed BMI and individual variables and multiple linear regression was used to investigate independent predictors of BMI overall and in sex-stratified analyses. RESULTS: Median BMI was significantly higher in females (28.7 kg/m(2)[95% CI 24.2-33.2] vs 23.0 kg/m(2)[95% CI 20.3-26.8];p < 0.001) with male sex associated with 17% lower BMI. In sex-stratified multiple linear regression models, compared to those never married, BMI was 7% higher in currently married males and 6% in currently married females. Current smoking in men and former smoking in women were associated with reductions in BMI of 13% and 26% respectively, compared with non-smokers. Higher educational attainment in women and higher socioeconomic status in men were both associated with higher BMI, while being HIV-positive and alcohol consumption in women were associated lower BMI. CONCLUSIONS: Female sex strongly predicts higher BMI in this rural African population. While some predictors of higher BMI differ by sex, married individuals in both sexes had a higher BMI, suggesting that, in addition to developing sex-specific interventions to combat overweight and obesity, targeting married couples may result in reduction in population BMI.