Long-term exposure to contaminated drinking water from shallow dug wells is widely suspected to be the cause of chronic kidney disease of unknown etiology (CKDu) which prevails in northcentral Sri Lanka. Although several hydrogeochemical studies have been conducted in this area, studies that have attempted robust statistical comparisons between waters consumed by CKDu-affected and CKDu-free communities within the endemic area are rare, and the causative agents of the disease remain elusive. We attempted to determine the hydrochemical differences between the groundwater consumed by CKDu-affected communities and that consumed by CKDu-unaffected communities living in the CKDu-endemic area based on a substantial new dataset that ensures the robustness of the statistical and graphical comparisons. The study revealed that SO42−, PO43−, NO3−, Sr, Mg, Ba, Pb, and Cu were significantly greater in CKDu-linked water and were positively correlated with the incidence of CKDu, indicating their causative role. Manganese and Zn levels were significantly lower in CKDu-linked water and were negatively correlated with CKDu-incidence, indicating an impeding effect. Our results agree with the elevated hardness and F− values reported in previous work. However, statistical and graphical comparisons do not support the widely speculated role of F− in the incidence of CKDu. Toxic metals and metalloids except for V occur at concentrations accepted as safe for human consumption. Subtle but significant contributions from several chemical constituents occurring in concentrations accepted to be safe and permissible could be interpreted as supporting evidence for the participatory role of multiple ions, probably imposing a deleterious synergistic effect.