Our study objective was to compare the relative effectiveness and efficiency of quadrat and capture-mark-recapture (CMR) sampling designs for monitoring mussels. We collected data on a recently reintroduced population of federally endangered Epioblasma capsaeformis and two nonlisted, naturally occurring species—Actinonaias pectorosa and Medionidus conradicus—in the Upper Clinch River, Virginia, over two years using systematic quadrat and CMR sampling. Both sampling approaches produced similar estimates of abundance; however, precision of estimates varied between approaches, years, and among species, and further, quadrat sampling efficiency of mussels detectable on the substrate surface varied among species. CMR modeling revealed that capture probabilities for all three study species varied by time and were positively associated with shell length, that E. capsaeformis detection was influenced by sex, and that year-to-year apparent survival was high (>96%) for reintroduced E. capsaeformis. We recommend that monitoring projects use systematic quadrat sampling when the objective is to estimate and detect trends in abundance for species of moderate to high densities (>0.2/m²), whereas a CMR component should be incorporated when objectives include assessing reintroduced populations, obtaining reliable estimates of survival and recruitment, or producing unbiased population estimates for species of low to moderate densities (≤0.2/m²).