We evaluated habitat conditions available to infauna and epifauna across a gradient of shoreline development within the Pascagoula River estuary, Missisippi, to determine whether habitat characteristics and biotic responses were influenced by the degree of surrounding alteration. Three zones were defined: (H) severe alteration, (M) intermediate alteration, and (L) natural conditions starting about 5 km upstream. Eleven water-quality and habitat variables were quantified for infaunal and epifaunal nekton as indicators of habitat quality adjacent to both “restricted” and hardened shore and “unrestricted” or marsh-edge shore within each impact zone. Epifaunal nekton richness (S) was consistently greater at unrestricted shore types than restricted ones, highest in zone M and lowest in zone H, whereas infaunal S did not vary among impact zones or between shore types. Cluster analysis showed epifaunal nekton assemblages from unrestricted shores in zones M and L were most similar to each other, whereas restricted shore infaunal assemblages from zones H and M linked at ∼70%. SIMPER analysis indicated infaunal composition was not dissimilar among zones or between shore types. In contrast, epifaunal nekton assemblages were dissimilar from one another because of the presence and density of Corophium louisianum and Hargeria rapax, two major fish prey items. Our data suggest the relative quality of marsh-edge habitat depends upon the surrounding landscape and that the simple presence of marsh habitat is not enough to ensure a high level of ecosystem health. Rather, it is the spatial arrangement of the marsh that markedly affects the system's health. It is apparent that even the smallest patch of marsh habitat supported a larger diversity of fauna than nearby restricted habitats, suggesting that it matters where a salt-marsh habitat patch (including restoration sites) is located along the landscape because it will influence habitat quality and connectivity and thus the composition of infauna and epifauna nekton assemblages.