The Clinch River is located in northeastern Tennessee (TN) and southwestern Virginia (VA) of the United States, and contains a diverse mussel assemblage of 46 extant species, including 20 species listed as federally endangered. To facilitate quantitative monitoring of the fauna, quadrat data were collected from 2004 to 2009 at 18 sites in the river, including 12 sites in TN and 6 sites in VA. Thirty‐eight mussel species were collected alive in total from quadrat samples taken annually at sites in the TN section of the river. Over the five‐year study period, mussel density averaged 25.5 m−2 at all sites sampled in TN. In contrast, mussel density averaged only 3.1 m−2 at sites sampled in VA. The best historical site in VA was Pendleton Island in Scott County, where mussel density was estimated as high as 25 m−2 in 1979, comparable to current densities recorded in TN. Mussel densities are now <1 m−2, indicating a collapse of the fauna. A severe reduction in mussel abundance has occurred in a 68‐km section of the river from St. Paul, VA, downstream to approximately Clinchport, VA (river kilometers 411.5‐343.3). While the environmental factors responsible for the faunal decline are largely unknown, they must have been severe and sustained to reduce such large populations to their current low levels. Long‐term water and habitat quality monitoring is needed to determine whether environmental degradation is still occurring in the river.