BACKGROUND: HIV and tuberculosis (TB) are the most common causes of death in South Africa. Antiretroviral therapy (ART) programmes should have had an impact on mortality rates. This study describes the impact of HIV, a Wellness (HIV/ART) programme and TB on population-wide trends in mortality and causes of death among South African platinum miners, from before the HIV epidemic into the ART era. METHODOLOGY/PRINCIPAL FINDINGS: Retrospective analysis was conducted using routinely-collected data from an open cohort. Mortality and causes of death were determined from multiple sources, including cardiorespiratory autopsy records. All-cause and cause-specific mortality rates were calculated by calendar year. 41,665 male miners were observed for 311,938 person years (py) with 3863 deaths. The all-cause age-standardised mortality rate increased from 5.9/1000 py in 1992 to 20.2/1000 py in 2002. Following ART rollout in 2003, annual mortality rates fluctuated between 12.4/1000 py and 19.3/1000 py in the subsequent 7 years. Half of all deaths were HIV-related and 21% were caused by TB. Half (50%) of miners who died of HIV after ART rollout had never been registered on the Wellness programme. TB was the most common cause of death in HIV positive miners, increasing from 28% of deaths in the pre-ART period to 41% in the post-ART period. CONCLUSIONS/SIGNIFICANCE: This population-based cohort experienced a rapid increase in mortality from 1996 to 2003 due to increases in HIV and TB mortality. Following ART rollout there was a decrease in mortality, but a steady decrease has not been sustained. Possible explanations for these trends include the changing composition of the workforce, maturation of the HIV epidemic, insufficient uptake of ART and an increase in the proportion of deaths due to TB. In order to make a significant and sustained reduction in mortality in this population, expanding and integrating HIV and TB care and treatment is essential.