The physiological significance of stepwise increase of energy during total parenteral nutrition (TPN) was studied in starved rats. The rats were divided into three groups, which received TPN in the form of a stepwise increase of energy (group I), TPN with full energy content from the outset (group II) or on ad libitum diet (group III). There was no change in the concentration of plasma glucose, GOT, GPT or urinary glucose during TPN in group I, but a significantly increased was seen in group H. Enlargement of the liver and marked accumulation of hepatic triglyceride and cholesterol were also observed in group II. The contents of hepatic microsomal enzymes including cytochrome P-450 and cytochrome b5 were low in group II even when the concentrations of plasma glucose, GOT and GPT had returned to the normal range. The contents of hepatic phospholipid and microsomal enzymes in groups I and II were lower than those in group III. These results suggest that a stepwise increase of energy is import in order to avoid liver damage, and that the contents of hepatic microsomal enzymes are decreased by TPN.