• Sulfide stress reduced cell viability and phagocytic rate of hemocyte in clams. • Sulfide stress causes microbiota dysbiosis in hemolymph. • Sulfide exposure increased opportunistic pathogens and decreased the probiotics. Sulfide are widely accumulated in aquatic environments under anaerobic conditions, which cause health problems of aquatic animals, yet their toxic effects to benthic bivalves are not well understood. We investigated the effects of sulfide on innate immunity of the blood clam Tegillarca granosa. Immunity-related indicators and hemolymph microbiota were investigated in the clams exposed to sulfide (via 10, 100 and 1000 μmol/L of Na 2 S) over a 7-day period. The results showed that cellular immune responses in T. granosa were affected by exposure to high sulfide concentration (1000 μmol/L Na 2 S), as indicated by total counts of hemocytes (THC), cell viability, ROS levels and phagocytic activities, suggesting that sulfide stress induces T. granosa more vulnerable to pathogen challenges. In addition, the Na 2 S-induced stress also reshaped the hemolymph microbial community structure of T. granosa that some original genera decreased, such as Lactobacillus, Desulfovibrio and Akkermansia ; some genera increased, such as Vibrio and Pseudoalteromonas in sulfide stress group. Sulfide exposure promoted the proliferation of opportunistic pathogen and reduced the diversity of microbial community in the hemolymph of T. granosa. In summary, sulfide stress had marked hemocytotoxicity, reduced immune-cell activity and increased bacterial infections in the blood clam. [ABSTRACT FROM AUTHOR]