During extreme drought conditions, mussel survival and habitat conditions were monitored weekly at nine locations representing a gradient in stream size in the lower Flint River basin, Georgia, USA. Cumulative unionid mortality ranged from 13 to 93% among sites, and was associated with low flow velocity (below 0.01 m/s) and dissolved oxygen concentrations below 5 mg/L. Species assemblages demonstrated differential mortality under declining dissolved oxygen conditions. Riffle and medium-large stream mussel assemblages had greater mortality than generalist assemblages under reduced dissoloved oxygen (DO < 5 mg/L). Mussel community composition at medium-sized sites shifted toward greater dominance of generalist species and lower proportions of riffle and medium-large stream species. At other sites, community structure changed little, likely due to the dominance of drought-resilient species in small streams and less detrimental changes in stream habitat conditions in large streams. Low flow conditions and severe drought adversely affected mussel distributions and assemblages, particularly in high diversity, medium-sized streams.