Cobalt-protoporphyrin administration to adult male rats results in an intense induction of hepatic heme oxygenase, a pronounced decline of cytochrome P-450 content in liver and associated metabolic abnormalities, including a dose-dependent decrease in weight gain and a marked decline in serum concentrations of testosterone without a compensatory increase in serum luteinizing hormone levels. These abnormalities persist for at least 5-6 weeks after a single subcutaneous dose of the metalloporphyrin (25 mumol/kg b.w.). Experiments with pair-fed control and metalloporphyrin-treated rats indicated that the androgenic dysfunction produced by cobalt-protoporphyrin is not causally related to the associated weight loss produced by the compound. Hepatic heme oxygenase activity was markedly induced by cobalt-protoporphyrin as expected; the enzyme activity was not altered in hypothalami of treated rats but was elevated (approximately 5-fold) in pooled pituitaries. However, despite the expected decrease in hepatic cytochrome P-450 content, no changes were noted in cytochrome P-450 content of hypothalami or pituitaries. In experiments in which the enhanced heme oxygenase activity produced in liver by cobalt-protoporphyrin was completely antagonized by tin-protoporphyrin, a competitive inhibitor of the enzyme, neither the endocrine suppression nor the weight loss produced by cobalt-protoporphyrin was altered. These phenomena were thus clearly dissociated from the effects of cobalt-protoporphyrin on heme oxygenase. Whether or not cobalt-protoporphyrin acts centrally to impair both appetite and endocrine control mechanisms could not be determined in these experiments, but remains a possible explanation of the novel actions of this synthetic heme analogue.