Freshwater mussels appear to be promising candidates for adaptive cluster sampling because they are benthic macroinvertebrates that cluster spatially and are frequently found at low densities. We applied adaptive cluster sampling to estimate density of freshwater mussels at 24 sites along the Cacapon River, WV, where a preliminary timed search indicated that mussels were present at low density. Adaptive cluster sampling increased yield of individual mussels and detection of uncommon species; however, it did not improve precision of density estimates. Because finding uncommon species, collecting individuals of those species, and estimating their densities are important conservation activities, additional research is warranted on application of adaptive cluster sampling to freshwater mussels. However, at this time we do not recommend routine application of adaptive cluster sampling to freshwater mussel populations. The ultimate, and currently unanswered, question is how to tell when adaptive cluster sampling should be used, i.e., when is a population sufficiently rare and clustered for adaptive cluster sampling to be efficient and practical? A cost-effective procedure needs to be developed to identify biological populations for which adaptive cluster sampling is appropriate.