1. Despite a heightened global concern for native mussels, fundamental research on mussel ecology in large rivers is lacking. These gaps in knowledge about where mussels occur, and why, are limiting habitat restoration activities. 2. Large-scale systematic surveys for native mussels in three reaches of the Upper Mississippi River documented mussel communities composed of 16–23 species and ranging from 2.9–4.5 live mussels m-2 that were actively recruiting new cohorts into their populations (87–100% of the species were found as juveniles 5 years old). Estimates of mean tissue biomass and production in these reaches ranged from 2.1–3.1 g C m-2 and 0.4–0.6 g C m-2year-1, respectively. 3. Mussels filtered a significant amount of water (range, 0.05–0.07 m3m-2d-1) over a 480 km reach of the Upper Mississippi River — amounting to a filtration rate of 53.1 million m3day-1. The filtration rate of mussels as a percentage of river discharge ranged from 0.5–1.4% at high flows (5% exceedance), from 1.5–4.4% at moderate flows (50% exceedance) and from 4.4–12.2% during low flows (95% exceedance). 4. Collectively, these data suggest that native mussels play an integral role in this ecosystem by sequestering suspended materials that can be used by other benthic organisms.