The biochemical mechanism involved in cadmium-induced cellular injury remains to be elucidated. Various theories have been proposed to account for this action, one of which is an interaction with reduced sulfhydryl (SH) groups of membranes. The ability of a known SH group reducing agent, dithiothreitol (DTT), to interact with cadmium-induced damage to isolated hepatocytes was investigated. Cadmium chloride produced a cytotoxic response similar to that previously demonstrated. When added just prior to cadmium chloride, DTT was found to protect against the metal-induced injury. If the cells were first exposed to cadmium for 15 min before DTT was added, it was found that the cells could be rescued from the ensuing expression of toxicity due to cadmium. This result was regardless of the fact that by 15 min the cells had accumulated a quantity of cadmium that was associated with cell injury. Furthermore, DTT did not exert its action by decreasing the amount of cadmium accumulation by the cells. Under some experimental conditions, an increased cadmium uptake in the presence of DTT was observed. While it is not clear as to whether the chelating or thiol reductive properties of DTT are of prime importance in the demonstrated protection, the data show that toxicity is not due to a simple, single irreversible interaction between cadmium and membrane SH groups.