Ethanol and imidazole have been shown to cause similar changes in the hepatic drug metabolizing enzymes of rabbit liver. The effects of these agents on hepatic monooxygenase activities were compared in the rat to test whether similar changes might also occur in this species. Ethanol feeding caused 4- to 5-fold increases in rates of the microsomal metabolism of aniline and p-nitrophenol, and smaller increases in rates of dealkylation of 7-ethoxycoumarin and aminopyrine. Ethanol doubled cytochrome P-450 content and increased the staining intensity of a polypeptide with an apparent molecular weight of 54,000 as determined by SDS polyacrylamide gel electrophoresis. Imidazole pretreatment also enhanced rates of the microsomal metabolism of 7-ethoxycoumarin and aminopyrine, but did not affect rates of aniline or p-nitrophenol hydroxylation. In addition, imidazole did not affect cytochrome P-450 content or the electrophoretic profile of microsomal polypeptides. Thus, the effects of ethanol and imidazole pretreatments on hepatic drug metabolism vary substantially between rabbits and rats.