Effects of chronic parenteral carbohydrate administration on hepatic microsomal enzyme activity were studied in the rat. Intraperitoneal injections of either glucose or fructose (2.88 g daily for 7 days) significantly decreased hepatic cytochrome P-450 content and ethylmorphine N-demethylase and aniline hydroxylase activities. By the 5th day, cytochrome P-450 content decreased to 70-76% and ethylmorphine N-demethylase activity to 66-69% of control values. Aniline hydroxylase activity was not significantly altered until the 7th day, by which time it was 77-79% of control values. In vivo assessment of hepatic drug-metabolizing capacity using antipyrine as a test drug confirmed these decreases observed in vitro. Two major conclusions of these experiments are that such variables as time and dose of carbohydrate administration can affect the magnitude of the changes produced and that each parameter measured exhibited a distinctive pattern of change with time. Chronic carbohydrate administration produced hepatic fatty infiltration and glycogen depletion. Since all groups received identical amounts of specific nutrients, fatty infiltration was probably due to increased lipogenesis with decreased hepatic oxidative metabolism of fat. During these experiments neither hypoinsulinemia nor increased levels of cyclic AMP were observed. The molecular mechanisms responsible for hepatic glycogen depletion and decreased MFO activities remain to be established.