Many rural communities in South Africa (SA) rely on the river water as their main source of drinking water. However, rivers are often polluted from industrial and wasterwater treatment plant discharges, so they may become contaminated in exceedance of safe-drinking water limits. The Olifants River is a major river in SA and has been increasingly polluted by mining discharges, dysfunctional waste water treatment plants, agricultural runoff, and land degradation in the most recent years. This river is transboundary river between SA and Mozambique and passes through hundreds of rural communities, not only providing the main source of drinking water for many but also contributing to the livelihood of families through providing water for subsistence agriculture. Many of individuals within these rural communities may be at risk for adverse health effects and infection especially individuals and households residing along the Olifants River who rely on the river water directly for domestic potable use. Children especially those under age five, as well as immunocompromised individuals (due to the high prevalence of HIV and TB in the region) may be at increased risk. The levels of heavy metals and E.coli found in the Olifants River often exceeded the safe drinking water levels set by international standards. This paper analyzes data from the National Monitoring Programme – surface water quality – provided by the Department of Water and Sanitation (SA) in order to conduct a human health risk assessment for oral ingestion of heavy metals (As, Al, Cd, Cu, Cr, Cr(VI), Hg, Pb, Ni, Zn) as well as the disease risk (as reflected by the indicator E.coli), for drinking waters from the middle part of the Olifants River Catchment. The goal is to help the local municipalities and governmental agencies in the region understand the risk of metals and waterborne disease to their citizens so that they may better manage the risk.