The US Geological Survey is conducting a study of surface-water quality in the Rocky Mountains of central Colorado, an area of approximately 55,000 km². Using new and existing geologic maps, the more than 200 rock formations represented in the area were arranged into 17 groups based on lithologic similarity. The dominant regional geologic feature affecting water quality in central Colorado is the Colorado mineral belt (CMB), a NE-trending zone hosting many polymetallic vein or replacement deposits, and porphyry Mo deposits, many of which have been mined historically. The influence of the CMB is seen in lower surface-water pH (<5), and higher concentrations of SO₄^{2 -} (>100 mg/L) and chalcophile metals such as Cu (>10 ??g/L), Zn (>100 ??g/L), and Cd (>1 ??g/L) relative to surface water outside the CMB. Not all streams within the CMB have been affected by mineralization, as there are numerous catchments within the CMB that have no mineralization or alteration exposed at the surface. At the regional-scale, and away from sites affected by mineralization, hydrothermal alteration, or mining, the effects of lithology on water quality can be distinguished using geochemical reaction modeling and principal components analysis. At local scales (100 s of km²), effects of individual rock units on water chemistry are subtle but discernible, as shown by variations in concentrations of major lithophile elements or ratios between them. These results demonstrate the usefulness of regional geochemical sampling of surface waters and process-based interpretations incorporating geologic and geochemical understanding to establish geochemical baselines.