As the human population in the piedmont of South Carolina grows, the release of treated effluents from wastewater-treatment plants (WWTPs) will increasingly affect the chemical composition and biogeochemical processes of the region's rivers. We examined the impact of WWTP effluent on the solute chemistry of one such river, the Bush River, South Carolina, which experienced extremely low flow during the drought of 1998–2002. Two WWTPs discharge into the river and accounted for at least 70% of the river flow during the summer of 2002. The response of river solute concentrations to discharge from the downstream WWTP followed the expected dilution pattern. In contrast, the response to discharge from the upstream WWTP only followed the expected pattern for nonnutrient solutes (e.g., chloride and sodium). Concentrations of total dissolved nitrogen, nitrate, phosphate, and sulfate were all far below those expected from simple mixing calculations. At downstream sampling localities, however, conservative ions such as chloride and sodium had concentrations well below those predicted by mixing calculations. Instream biological processes associated with very low flow conditions, such as denitrification and sulfate reduction, may have caused the observed decrease in some nutrients. The cause of the discrepancy between the observed and predicted concentrations of conservative solutes remains unclear. Fluxes of solutes were much higher below the downstream WWTP. Our results indicate that the treated effluents of WWTPs have a significant impact on the biogeochemistry of piedmont rivers during drought periods. The impact is particularly large in rivers with small discharges. Extreme low flow conditions, however, may actually increase the opportunity for biological activity to remove dissolved nutrients from river water.