High prevalence of chronic kidney disease of unknown etiology (CKDu) in some regions of the world is suspected mainly due to a toxin-mediated renal failure. We examined the incidence of CKDu and potable chemical water quality in a CKDu-affected region. This region has been identified as a high-risk zone for CKDu (location: latitude: 8.3500°-9.0000°, longitude: 80.3833°-81.3000°, North Central Province, NCP, Sri Lanka) by the World Health Organization (WHO). However, within this macro-region, small pockets of CKDu non-prevalence zones do exist; notably, the residents in those pockets consume spring water. Therefore, the drinking water quality of four areas, namely high-CKDu-prevalence areas (zone I), low-CKDu-prevalence area (zone II), the CKDu-free isolated pockets (zone III) and control areas (controls) were examined for F, Al, Cd, and As, and hardness and the statistical analysis were carried out to probe possible correlations among these parameters. The fluoride and hardness concentrations of water in zone III and control areas are much lower compared to zones I and II, and the water hardness is ~61 mg/L CaCO3. In zones I and II, the harness of drinking water is ~121-180 mg/L CaCO3; however, Al, Cd and As concentrations are almost comparable and below WHO recommendations. In most of the locations in zones I and II, the F concentration in drinking water is higher than the WHO recommendations. The peculiar distribution patterns of CKDu point to a synergic effect of trace elements in water for etiology of the disease.