Background Malaria remains a serious epidemic threat in the Lowveld region of Mpumalanga Province. In order to appropriately target interventions to achieve substantial reductions in malaria morbidity and mortality, there is a need to assess the impact of current control interventions such as indoor residual spraying (IRS) for vector control. This study aimed to assess long-term changes in the burden of malaria in Mpumalanga Province during the past eight years (2001-2009) and whether IRS and climate variability had an effect on these changes. Methods All malaria cases and deaths notified to the Malaria Control Programme, Department of Health was reviewed for the period 2001 to 2009. Data were retrieved from the provincial Integrated Malaria Information System (IMIS) database. Climate and population data were obtained from the South Africa Weather Service and Statistics South Africa, respectively. Descriptive statistics were computed to determine any temporal changes in malaria morbidity and mortality. Autoregressive integrated moving average (ARIMA) models were developed to assess the effect of climatic factors on malaria. Results Within the eight-year period of the study, a total of 35,191 cases and 164 deaths-attributed to malaria were notified in Mpumalanga Province. There was a significant decrease in the incidence of malaria in Mpumalanga Province from 385 in 2001/02 to 50 cases per 100,000 population in 2008/09 (P < 0.005). The overall incidence and case fatality rates were 134 cases per 100,000 and 0.54%, respectively. Malaria incidence and case fatality rate by gender showed significant differences, higher in males than in L.M. Ngomane University of Pretoria, 2012 iv females (166.9 versus 106.4; P < 0.001; CFR 0.41% versus 0.55%). The incidence of malaria increased from age 5-14 years (70), reaching a peak at age 25-34 years (190), declining thereafter (50 in those >65 years). Mortality due to malaria was higher in those >65 years, the mean CFR reaching a 2.1% peak. Almost half (47.8%) of the notified cases originated from Mozambique and Mpumalanga Province itself constituted 50.1%. The distribution of malaria varied across the districts, highest in Ehlanzeni district (96.5%), lowest in Nkangala (<1%) and Gert Sibande (<1%). A notable decline in malaria case notification was observed following the increased IRS coverage from 2006/07 to 2008/09 malaria seasons. A distinct seasonal transmission pattern was found to be significantly related to changes in rainfall patterns (P = 0.007). Conclusion Decades of continuous IRS with insecticides have proved to be successful in reducing the burden of malaria morbidity and mortality in Mpumalanga Province between 2001 and 2009. A decline of above 50% in malaria morbidity and mortality was observed following expanded IRS coverage. These results highlight the need to continue with IRS together with other control strategies until interruption in local malaria transmission is completely achieved and alternative vector control strategies implemented. Efforts need to be directed towards the control of imported cases, interruption of local transmission and focus on research into sustainable and cost-effective combination of control interventions.