Estimating the annual mass flux at a network of fixed stations is one approach to characterizing water quality of large rivers. The interpretive context provided by annual flux includes identifying source and sink areas for constituents and estimating the loadings to receiving waters, such as reservoirs or the ocean. Since 1995, the US Geological Survey's National Stream Quality Accounting Network (NASQAN) has employed this approach at a network of 39 stations in four of the largest river basins of the USA: The Mississippi, the Columbia, the Colorado and the Rio Grande. In this paper, the design of NASQAN is described and its effectiveness at characterizing the water quality of these rivers is evaluated using data from the first 3 years of operation. A broad range of constituents was measured by NASQAN, including trace organic and inorganic chemicals, major ions, sediment and nutrients. Where possible, a regression model relating concentration to discharge and season was used to interpolate between chemical observations for flux estimation. For water-quality network design, the most important finding from NASQAN was the importance of having a specific objective (that is, estimating annual mass flux) and, from that, an explicitly stated data analysis strategy, namely the use of regression models to interpolate between observations. The use of such models aided in the design of sampling strategy and provided a context for data review. The regression models essentially form null hypotheses for concentration variation that can be evaluated by the observed data. The feedback between network operation and data collection established by the hypothesis tests places the water-quality network on a firm scientific footing.