The heavy metal, cadmium, is a potent inhibitor of the hepatic microsomal monooxygenase enzyme system in male, but not female, rats. The selectivity of this inhibitory effect of Cd was further examined by utilizing rats treated with inducers of this drug metabolizing enzyme system. Animals received phenobarbital (PB) sodium (100 mg/kg, ip, 72, 48, and 24 hr before sacrifice), or 3-methylcholanthrene or benzo[ a]pyrene (20 mg/kg, ip, 72 and 48 hr prior to sacrifice) as inducers. Designated groups of these animals also received cadmium (1.0 mg Cd 2+/kg), ip) either 120 or 72 hr before sacrifice. Noninduced male rats exhibited significant decreases in cytochrome P-450 content and drug-metabolizing enzyme activity following Cd treatment. The magnitude of the reductions in drug-metabolizing enzyme activity produced by Cd paralleled the magnitude of the sex difference in biotransformation of the substrate examined. Phenobarbital-treated male rats receiving a simultaneous Cd injection (72 hr prior to sacrifice) were also sensitive to Cd-induced inhibitions in cytochrome P-450 content and monooxygenase activity, although the extent of the reductions produced by Cd in PB-treated animals was less than that observed in noninduced male rats. In PB-treated male rats receiving a prior dose of Cd (120 hr before sacrifice), only the metabolism of the highly sex-dependent substrate, ethylmorphine, was significantly reduced. Cytochrome P-448 levels, and cytochrome P-448-mediated biotransformations which are elevated following hydrocarbon treatment, were not decreased by either simultaneous or prior Cd administration to male rats. Control, PB-treated, and hydrocarbon-treated female rats were not susceptible to Cd-induced reduction in hemoprotein content or inhibition of drug-metabolizing enzyme activity with the exception of those animals receiving both benzo[ a]pyrene and Cd, which displayed slight but significant reductions in the oxidation of sex-dependent substrates. These results demonstrate the selective nature of the inhibitory effects of Cd upon drug metabolism in the rat.