A wastewater reuse model was applied to the Upper Colorado River basin to assess the (1) percent of accumulated wastewater (ACCWW%) from municipal and industrial wastewater treatment plants (WWTPs) in each initialized (that is, has an assigned hydrosequence number for flow-routing) National Hydrography Dataset Version 2.1 (NHDPlus V2.1) stream segment; and (2) predicted environmental concentrations (PECs, in nanograms per liter) of eight per-and polyfluoroalkyl substances (PFAS) as well as the sum of the eight PFAS. Model inputs included (1) NHDPlus V2.1 stream geometry and hydrologic information (Table 1); (2) WWTP information, provided by the U.S. Environmental Protection Agency (Table 2), including average daily effluent discharges and outfall locations; and (3) measured municipal wastewater effluent PFAS concentrations (Table 4) used to calculate PECs. Outfall locations were linked to the corresponding NHDPlus V2.1 stream segment receiving the effluent prior to calculating ACCWW%. ACCWW% values were calculated for years 2007 to 2020 using mean-monthly and mean-annual NHDPlus V2.1 gage-adjusted Enhanced Runoff Method streamflow estimates. PFAS PECs were calculated for 2020 using mean-annual NHDPlus V2.1 gage-adjusted Enhanced Runoff Method streamflow estimates. PFAS PECs were calculated from accumulated wastewater from sewerage system facilities (Standard Industrial Classification code 4952, i.e. ‘municipal’) as well as potential PFAS-handling industry sectors defined by the Environmental Protection Agency (U.S. Environmental Protection Agency, 2023). Model estimates at a stream reach of interest represent the combined total upstream wastewater discharges as well as direct discharges into the segment. R (version 4.4.1) and Python (version 3.9.16) scripts were used to summarize wastewater inputs from outfall locations by COMID and route and accumulate each wastewater and predicted contaminant loads while accounting for in-stream dilution. Any users of these data should review the entire metadata record and the associated manuscript (see Larger Work Citation). See 'Distribution liability' statements for more information.