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Hundreds of domestic wells in northern New Mexico, have concentrations of U, As, and NO3- that exceed the Environmental Protection Agency’s (EPA) maximum contaminant level (MCL) for drinking water consumption. As part of a case study in groundwater quality, we collected groundwater samples from 749 domestic wells throughout the eastern half of the Espanola Basin. All water samples were analyzed for major ions, trace metals, and alkalinity. Selected samples were also analyzed for stable isotopes of O, H, and N. Of the wells we measured, 15, 173, and 99 had respective NO3-, U, and As concentrations that exceeded the EPA’s MCL. Total dissolved solids (TDS), U, and HCO3- were elevated in the Sangre de Cristo mountain block and around the town of Nambe. Our findings suggest that roll-front U deposits and devitrification of volcanic ash result in elevated U near Nambe,while weathering of granitic rocks accounts for high U in the mountain block. Arsenic concentrations were high in much of the study area with the exception of the Santa Fe metro region and the mountain block. Elevated As concentrations can be explained by devitrification of volcanic ash, anion exchange with clays, and mixing with hydrothermal fluids. In wells with high NO3- concentrations, analysis of N isotopes are consistent with contamination from domestic wastewater effluent. Our findings suggest that the geochemistry of the region is largely influenced by local geology while groundwater contamination from domestic water treatment and wastewater effluent is an emerging issue.