INTRODUCTION: Despite global progress, there remains a disproportionate burden of under-five year old deaths in sub-Saharan Africa (SSA), where four out of five child deaths occur. Substantial progress has been made in improving sanitation, controlling communicable diseases and the spread of HIV in most parts of the world. However, significant strides to address some key risk factors related to under-five mortality are still needed in rural SSA if they are to attain relevant 2030 SDG targets. The aim of this study is to investigate the risk factors for under-five mortality in an HIV hyper-endemic area of rural South Africa, from 2000-2014. Some of the key risk factors investigated are, for example: household wealth, source of drinking water, distance to the national road and birth order. METHODS: We conducted a statistical analysis of 759 births from a population-based cohort in rural KwaZulu-Natal Province, South Africa, from 2000 to 2014. A Cox Proportional Hazards model was used to identify the risk factors and key socio-demographic correlates of under-five mortality leveraging the longitudinal structure of the population cohort. RESULTS: Child mortality rates declined by 80 per cent from 2000 to 2014, from >140 per 1,000 persons in years 2001-2003 to 20 per 1,000 persons in the year 2014. The highest under-five mortality rate was recorded in 2002/2003, which decreased following the start of antiretroviral therapy rollout in 2003/4. The results indicated that under-five and infant mortality are significantly associated with a low wealth index of 1.49 (1.007-2.48) for under-fives and 3.03 (1.72-5.34) for infants. Children and infants with a lower wealth index had a significantly increased risk of mortality as compared to those with a high wealth index. Other significant factors included: source of household drinking water (borehole) 3.03 (1.72-5.34) for under-fives and 2.98 (1.62-5.49) for infants; having an HIV positive mother 4.22 (2.68-6.65) for under-fives and 3.26 (1.93-5.51) for infants, and period of death 9.13 (5.70-14.6) for under-fives and 1.28 (0.75-2.20) for infants. Wealth index had the largest population attributable fraction of 25.4 per cent. CONCLUSIONS: The research findings show a substantial overall reduction in under-five mortality since 2003. Unsafe household water sources and having an HIV-positive mother were associated with an increased risk of under-five mortality in this rural setting. The significant risk factors identified align well with the SDG 2030 targets for reducing child mortality, which include improved nutrition, sanitation, hygiene and reduced HIV infections. Current trajectories suggest that there is some hope for meeting the 2030 SGD targets in rural South Africa and the region if the identified significant risk factors are adequately addressed.