The levels of cytochrome P-450, cytochrome b5, aminopyrine N-demethylase, and benzo[a]pyrene hydroxylase were depressed in hepatic microsomes following treatment of mice with the interferon inducer poly rI.rC. The decrease in the hepatic mixed function oxidase system was accompanied by an increase in the incorporation of amino acids into total microsomal protein. Fractionation of solubilized microsomes using a Sephacryl S-200 gel filtration column demonstrated that the increase in amino acid incorporation tended to be associated with proteins with molecular weights under 67 000. The fractions which contained cytochrome P-450 were further separated using a DEAE cellulose column. The amount of labelled amino acids associated with the cytochrome P-450 fractions was uniformly depressed in preparations from poly rI.rC treated animals compared with saline-treated controls. These results suggest that poly rI.rC causes a depression in the rate of synthesis of the apoprotein of cytochrome P-450 while increasing the incorporation of amino acids into other hepatic proteins. The decrease in apocytochrome P-450 synthesis explains the marked loss of drug biotransformation which occurs following induction of interferon.