Spatial distributions and patchiness of dominant megafaunal invertebrates in deep-sea seep environments may indicate heterogeneities in the flux of reduced chemical compounds. At the Blake Ridge seep off South Carolina, USA, the invertebrate assemblage includes dense populations of live vesicomyid clams (an undescribed species) as well as extensive clam shell beds (i.e. dead clams). In the present study, we characterized clam parameters (density, size-frequency distribution, reproductive condition) in relation to sulfur chemistry (sulfide and sulfate concentrations and isotopic compositions, pyrite and elemental sulfur concentrations) and other sedimentary metrics (grain size, organic content). For clams >5 mm, clam density was highest where the total dissolved sulfide concentration at 10 cm depth (ΣH₂S_10cm) was 0.4 to 1.1 mmol l^–1; juvenile clams (<5 mm) were most dense where ΣH₂S_10cm was lowest. Clams were reproductively capable across a broad range of ΣH₂S_10cm (0.1 to 6.4 mmol l^–1), and females in the sampled populations displayed asynchronous gametogenesis. Sulfide concentrations in porewaters at the shell–sediment interface of cores from shell beds were high, 3.3 to 12.1 mmol l^–1, compared to <1 mmol l^–1 sulfide concentrations at the clam–sediment interface in live clam beds. Concentration profiles for sulfide and sulfate in shell beds were typical of those expected where there is active microbial sulfate reduction. In clam beds, profiles of sulfide and sulfate concentrations were also consistent with rapid uptake of sulfide by the clams. Sulfate in shell beds was systematically enriched in ³⁴S relative to that in clam beds due to microbial fractionation during sulfate reduction, but in clam beds, sulfate δ³⁴S matched that of seawater (~20‰). Residual sulfide values in clam and shell beds were correspondingly depleted in ³⁴S. Based on porewater sulfide concentrations in shell beds at the time of sampling, we suggest that clam mortality may have been due to an abrupt increase in sulfide concentration and sulfide toxicity, but other alternatives cannot be eliminated.