Unionid mussels are critical to aquatic ecosystem function and are imperiled. They are indicators of biological integrity due to sensitivity to stressors and interconnectedness with the aquatic community. Like unionids, invasive sea lamprey larvae (Petromyzon marinus) burrow into stream sediments. Sea lampreys have seriously impacted the ecology of the Great Lakes. Sea lamprey control consists of lampricides targeting the larval stage (ammocoetes) in tributaries. Lampricides have sublethal effects on mussels. This study investigated mussel and ammocoete distribution and habitat use to aid in refining lampricide application. Habitat and mussel surveys were conducted in the Paw Paw River, in Southwest Michigan, and ammoceote data were obtained from databases of sea lamprey surveys conducted by the US Fish and Wildlife Service. Mussels were absent in most tributaries and had a mean density of 0.59/m² in the mainstem. Ammocoetes had a mean density of 0.43/m² and densities were highest in tributaries. A statewide regression analysis revealed that mussels have species specific distribution determinants and a canonical correspondence analysis demonstrated this species specific pattern in the Paw Paw River. Generalized linear models revealed median particle size, gradient, and bank stability to be effective predictors of unionid distribution in the Paw Paw River. Distance to sea lamprey spawning habitat and bank stability were effective predictors of ammocoete distribution. Minimal overlap of mussel and ammocoete distributions suggests that refinement of lampricide treatment in the Paw Paw River is possible. Redefining the extent of the mainstem reach and dividing it into several shorter reaches so that only areas with high ammocoete densities and low unionid densities would be treated with lampricide could result in reducing treatment costs and minimizing threats to unionid conservation while still having continued success in controlling sea lamprey.