The benthic macrofaunal community of the Mullica River–Great Bay estuary in the Jacques Cousteau National Estuarine Research Reserve is characterized by both small-scale and large-scale distribution patterns that can be correlated to gradients in physicochemical parameters. Sediment composition is a major factor regulating the local distribution of benthic assemblages in the estuary, with the amount of silt-clay being particularly important. For example, one suite of benthic fauna (i.e., Ampelisca verrilli, Ensis directus, Haustorius arenarius, Pygospio elegans, and Oxyurostylis smithi) reported in the estuary has been found only in sediments with less than 20% silt-clay, whereas another (i.e., Acteocina canaliculata, Lumbrineris tenuis, Maldinopsis elongata, Tellina agilis, Turbonilla sp., and Unciola irrorata) has been observed only in sediments with more than 38% silt-clay. Other physicochemical factors (e.g., organic carbon content of the sediments, dissolved oxygen levels, bottom currents, and turbidity) might also influence the local distribution patterns of the fauna. On the estuary scale, environmental gradients from upriver to down-bay regions strongly affect the distribution of the benthos over broader spatial areas. Hence, four distinct regional assemblages of benthic invertebrates have been identified in the Mullica River–Great Bay estuary, including river-, bay-, lower bay–, and estuary-wide forms. The dominant assemblage—the estuary-wide forms distributed along the length of the estuary—consists of the most abundant populations with the widest salinity tolerances. Examples are Ampelisca abdita, Corophium cylindricum, Cyathura polita, Notomastus latericeus, Polydora ligni, Scoloplos robustus, and Turbonilla sp. Because Great Bay exhibits marked changes in sediment type from predominantly sands in the eastern perimeter to generally finer deposits along the western margin, the abundance, species richness, and species composition of benthic invertebrates vary considerably over relatively small spatial scales.