The lampricides TFM (3-trifluoromethyl-4′-nitrophenol) and Niclosamide (NIC, 2′, 5-dichloro-4′-nitrosalicylanilide) are used to control sea lamprey populations in the Great Lakes and associated tributaries. Niclosamide is often used as an additive to TFM to reduce the amount of TFM required to control sea lamprey. Concern is growing over the risk that lampricide treatments pose to native freshwater mussels residing in streams. Our objectives were to determine the acute toxicity of TFM and TFM:NIC to free glochidia (removed from the marsupial gills), compare the relative toxicity of TFM and TFM:NIC between free glochidia and brooded glochidia (within the marsupial gills), determine if glochidia age influences toxicity, and assess if exposure of gravid mussels to TFM and TFM:NIC alters behavior and reproduction. Three acute toxicity tests (2:TFM, 1:TFM : NIC) were conducted with glochidia and adults of the plain pocketbook mussel (Lampsilis cardium). In tests with glochidia, viability did not differ across TFM and TFM : NIC concentrations that encompassed typical stream treatments. Glochidia age influenced toxicity as glochidia obtained later in the brooding season were less viable than glochidia obtained earlier in the brooding season. Exposure of adults to elevated concentrations of lampricides often resulted in behavioral effects, but rarely affected reproductive endpoints. Because mussels are long-lived (30 to 100 y), even intermittent and short duration exposures may cumulatively affect mussels over their lifetime. The risks posed by lampricide treatments in the Great Lakes would be further informed by research on the sublethal effects of lampricides, particularly effects on non-target organisms such as mussels.