Respiration of plume tissue of the hydrothermal vent tube worm Riftia pachyptila is insensitive to sulfide poisoning in contrast to tissues of animals that do not inhabit vents. Permeability barriers may not be responsible for this insensitivity since plume homogenates are also resistant to sulfide poisoning. Cytochrome c oxidase of plume, however, is strongly inhibited by sulfide at concentrations less than 10 µM. Factors present in blood, but not in cytosol, prevent sulfide from inhibiting cytochrome c oxidase. Avoidance of sulfide poisoning of respiration in Riftia pachyptila thus appears to involve a blood-borne factor having a higher sulfide affinity than that of cytochrome c oxidase, with the result that appreciable amounts of free sulfide are prevented from accumulating in the blood and entering the intracellular compartment.