BACKGROUND: In this study we analysed the spatial and temporal changes in patterns of mortality over a period when antiretroviral therapy (ART) was rolled out in a rural region of north-eastern South Africa. Previous studies have identified localised concentrated HIV related sub-epidemics and recommended that micro-level analyses be carried out in order to direct focused interventions. METHODS: Data from an ongoing health and socio-demographic surveillance study was used in the analysis. The follow-up was divided into two periods, 2007-2008 and 2009-2010, representing the times immediately before and after the effects on mortality of the decentralised ART provision from a newly established local health centre would be expected to be evident. The study population at the start of the analysis was approximately 73 000 individuals. Data were aggregated by village and also using a 2 × 2 km grid. We identified villages, grid squares and regions in the site where mortality rates within each time period or rate ratios between the periods differed significantly from the overall trends. We used clustering techniques to identify cause-specific mortality hotspots. FINDINGS: Comparing the two periods, there was a 30% decrease in age and gender standardised adult HIV-related and TB (HIV/TB) mortality with no change in mortality due to other causes. There was considerable spatial heterogeneity in the mortality patterns. Areas separated by 2 to 4 km with very different epidemic trajectories were identified. There was evidence that the impact of ART in reducing HIV/TB mortality was greatest in communities with higher mortality rates in the earlier period. CONCLUSIONS: This study shows the value of conducting high resolution spatial analyses in order to understand how local micro-epidemics contribute to changes seen over a wider area. Such analyses can support targeted interventions.