Summary Background In southern Africa, a substantial health transition is underway, with the heavy burden of chronic infectious illness (HIV/AIDS and tuberculosis) paralleled by the growing threat of non-communicable diseases. We investigated the extent and nature of this health transition and considered the implications for primary health care. Methods Health and sociodemographic surveillance started in the Agincourt subdistrict, rural South Africa, in 1992. In a population of 70 000, deaths (n=6153) were rigorously monitored with a validated verbal autopsy instrument to establish probable cause. We used age-standardised analyses to investigate the dynamics of the mortality transition by comparing the period 2002–05 with 1992–94. Findings Mortality from chronic non-communicable disease ranked highest in adults aged 50 years and older in 1992–94 (41% of deaths [123/298]), whereas acute diarrhoea and malnutrition accounted for 37% of deaths (59/158) in children younger than 5 years. Since then, all-cause mortality increased substantially (risk ratio 1·87 [95% CI 1·73–2·03]; p<0·0001) because of a six-fold rise in deaths from infectious disease affecting most age and sex groups (5·98 [4·85–7·38]; p<0·0001), and a modest increase in deaths from non-communicable disease (1·15 [0·99–1·33]; p=0·066). The change in female risk of death from HIV and tuberculosis (15·06 [8·88–27·76]; p<0·0001) was almost double that of the change in male risk (8·13 [5·55–12·36]; p<0·0001). The burden of disorders requiring chronic care increased disproportionately compared with that requiring acute care (2·63 [2·30–3·01]; p<0·0001 vs 1·31 [1·12–1·55]; p=0·0003). Interpretation Mortality from non-communicable disease remains prominent despite the sustained increase in deaths from chronic infectious disease. The implications for primary health-care systems are substantial, with integrated chronic care based on scaled-up delivery of antiretroviral therapy needed to address this expanding burden. Funding The Wellcome Trust, UK; University of the Witwatersrand, Medical Research Council, and Anglo American and De Beers Chairman's Fund, South Africa; the European Union; Andrew W Mellon Foundation, Henry J Kaiser Family Foundation, and National Institute on Aging, National Institutes of Health, USA.