As part of the National Water-Quality Assessment (NAWQA) Program, the U.S. Geological Survey (USGS) monitored two sites on the main-stem South Platte River? an urban site in Denver and a mixed urban/agricultural site near Kersey?to determine changes in nutrient and pesticide concentrations from 1994 through 2000. Concentrations of nitrate, nitrite, ammonia, and orthophosphorus decreased at the Denver site during the study period, likely due to an increase in instream dilution of wastewater-treatment plant (WWTP) discharge and upgrades at the WWTPs. In contrast, only concentrations of orthophosphorus decreased at the Kersey site; agricultural inputs between Denver and Kersey may have offset the observed decreases in other nutrients upstream. During the extreme low-flow conditions in 1994, when there was relatively little snowmelt to dilute instream pesticide concentrations, total median pesticide concentrations at both sites were the highest of the study period. During the less extreme conditions in 1997 through 2000, greater amounts of snowmelt likely led to lower total median pesticide concentrations at both sites. Because pesticide-use data are not available, the contribution of changes in the amount and type of pesticides applied on the land to changes in the concentration of pesticides in the river is not known but likely was substantial. In general, insecticides predominated at the Denver site, whereas herbicides predominated at the Kersey site.