The in vitro inhibitory effects of heavy metals, i.e., mercury, cadmium, lead, nickel and beryllium in their chloride forms, on rabbit pulmonary drug-metabolizing enzymes were studied comparatively. Microsomal and cytosolic fractions prepared from rabbit lungs were incubated in the presence of heavy metals prior to enzyme assays. Mercury was the most potent in reducing cytochrome P450 content and mixed-function oxidase activities including NADPH-cytochrome c reductase and benzo[a]pyrene hydroxylase. The addition of mercury to pulmonary microsomal preparations resulted in a spectral shift from 450 nm to 420 nm in an absorption maximum of cytochrome P450-carbon monoxide complex with mercury chloride being more potent than methylmercury. Cadmium was also inhibitory, while the effects of nickel were noted only at higher concentrations. Neither lead nor beryllium was inhibitory. Among second-phase drug-metabolizing enzymes, UDP-glucuronyltransferase and glutathione S-transferase were found to be susceptible to the adverse effects of mercury and lead, respectively. The extent of inhibition of the latter activity by mercury were highly dependent on the concentration of glutathione, implying the complex formation between them. Cadmium was slightly inhibitory to both enzyme activities, though the other metals had no effect. The results indicate that the pulmonary toxicities of airborne heavy metals could be inferred using simple in vitro assays.