To assess the impact of zebra and quagga mussel (Dreissena spp.) infestation on unionids, unionids (Bivalvia: Unionidae) were sampled in the Detroit River in 1982–1983, before mussels invaded the river, and in 1992 and 1994, after mussels invaded the river. Live unionids at four stations along the southeastern shore accounted for 97% (20 species) of all shells collected in 1982–1983, whereas live unionids accounted for only 10% (13 species) in 1992. A similar decline in live unionids occurred at nine stations along the northwestern shore, except the decline occurred over the three sampling periods: in 1982–83, 84% (22 species) were live; in 1992, 65% (26 species) were live; and, in 1994, only 3% (13 species) were live. The difference in time to near-total mortality of unionids along the southeastern and northwestern shores is attributed to differences in the time of invasion and abundance of zebra mussel veligers in distinct water masses emanating from Lake St. Clair located immediately upstream of the Detroit River. Although individuals of all species of all unionid subfamilies declined between 1982 and 1992/1994, members of the subfamilies Anodontinae and Lampsilinae declined more than Ambleminae. Between 1986 and 1992/1994, five Anodontinae, three Lampsilinae and 0 Ambleminae species have been extirpated from the river due to dreissenid mussel infestation. Numbers of individuals of commonly found species declined more than numbers of individuals of uncommonly found species. However, the number of uncommon species declined 47% (17 to 9) along both the southeastern and northwestern shores, whereas common species remained the same (3 species) along the southeastern shore and declined only 40% (5 to 3 species) along the northwestern shore. This study, and others, suggest that high mortality of unionids can occur between 4 and 6 yr after initial invasion by dreissenids or up to 8 yr depending on water current patterns. Infestation-induced mortality of unionids in the Detroit River is similar to that observed at a few locations in other rivers, but is higher over a larger area than that measured in other rivers to date, probably because the Detroit River was the first to be colonized by dreissenid mussels in North America.