In arid and semi-arid regions, many rivers experience extremely low flow conditions during seasonal dry periods. During these times, effluent from wastewater treatment plants can make up the majority of flow in the river. However, water quality in urban systems can also be strongly influenced by the natural or human-influenced flow regime and discharge from other anthropogenic sources such as industrial operations and runoff from impervious surfaces. In this study, we aimed to determine whether water quality was controlled primarily by wastewater discharge in an effluentdominated river. Between May 2016-May 2019, we systematically measured water temperature, pH, dissolved oxygen, biochemical oxygen demand, and the concentrations of nitrate-N, ammonia-N, and orthophosphate in the South Platte River in the Denver metropolitan area, Colorado, USA. We found that, despite being an effluentdominated river, wastewater treatment plant discharge was not the principal factor controlling water quality in many of the sampled areas. Non-point source pollution from impervious surfaces, delivered to the river through storm drains and minor tributary streams, also contributed to the high nutrient conditions in several locations. We also noted a strong seasonality in water quality, with higher concentrations of nutrients and higher biochemical oxygen demand in the winter months when wastewater effluent can make up more than 90% of the flow in the river. Thus, the interaction of discharge location and reduced seasonal flow produced spatio-temporal hot spots of diminished water quality. More stringent enforcement of water quality regulations may improve water quality in this system. However, a large portion of the pollution seems to be from non-point sources, which are very difficult to control.