The effects of chronic ethanol consumption and variations in dietary protein content on microsomal drug metabolism were studied in rats pair-fed liquid diets containing 10, 20, or 30% dietary protein with or without ethanol. In vivo drug metabolism was measured by aminopyrine breath tests and aminopyrine blood elimination kinetics. In vitro drug metabolism was assessed by measuring aminopyrine N-demethylase activity in the hepatic microsomal fraction. The rate of elimination of aminopyrine in vivo was increased in all ethanol-fed animals (p < 0.05) regardless of the protein content of the diet. Animals receiving 10 or 20% protein diets with ethanol showed a 36% increase in drug elimination over pair-fed controls as compared to a 17% increase in drug elimination over controls in animals receiving 30% protein diets. Microsomal aminopyrine N-demethylase activities were similar in ethanol-fed animals and pair-fed controls. Cytochrome P-450 content was increased in all ethanol-fed animals (p < 0.05) but the increase was not dependent on dietary protein content. These results indicate that the effect of chronic ethanol feeding in enhancing drug metabolism in vivo is influenced by the dietary protein content.