The watershed of the Neuse River, a major tributary of the largest lagoonal estuary on the U.S. mainland, has sustained rapid growth of human and swine populations. This study integrated a decade of available land cover and water quality data to examine relationships between land use changes and surface water quality. Geographic Information Systems (GIS) analysis was used to characterize 26 subbasins throughout the watershed for changes in land use during 1992-2001, considering urban, agricultural (cropland, animal as pasture, and densities of confined animal feed operations [CAFOs]), forested, grassland, and wetland categories and numbers of wastewater treatment plants (WWTPs). GIS was also used together with longitudinal regression analysis to identify specific land use characteristics that influenced surface water quality. Total phosphorus concentrations were significantly higher during summer in subbasins with high densities of WWTPs and CAFOs. Nitrate was significantly higher during winter in subbasins with high numbers of WWTPs, and organic nitrogen was higher in subbasins with higher agricultural coverage, especially with high coverage of pastures fertilized with animal manure. Ammonium concentrations were elevated after high precipitation. Overall, wastewater discharges in the upper, increasingly urbanized Neuse basin and intensive swine agriculture in the lower basin have been the highest contributors of nitrogen and phosphorus to receiving surface waters. Although nonpoint sources have been emphasized in the eutrophication of rivers and estuaries such as the Neuse, point sources continue to be major nutrient contributors in watersheds sustaining increasing human population growth. The described correlation and regression analyses represent a rapid, reliable method to relate land use patterns to water quality, and they can be adapted to watersheds in any region.