It is now generally accepted that fat emulsions are an efficient energy source during total parenteral nutrition (TPN). However, there is debate about how this fat should be prescribed. Some authorities prescribe fat as an intermittent infusion, alternating fat and carbohydrate, whereas others prefer a continuous infusion, giving fat simultaneously with carbohydrate. This 6-day crossover study examined the substrate-hormonal profiles of 10 patients in response to two isocaloric and isonitrogenous TPN regimens. In regimen A (intermittent), equicaloric volumes of 25% glucose and 10% Intralipid as energy sources were alternated every 12 h. During regimen B (continuous), the total nonprotein calories given each day was the same as in regimen A, but glucose and fat were infused simultaneously over every 24-h period. Amino acids were infused continuously throughout the study period in all patients. Blood samples were taken every 12 h. Wide fluctuations in insulin and all substrates occurred during regimen A. Persistent hyperinsulinemia throughout regimen A may have impaired the oxidation of exogenous fat. The substrate-hormonal profiles observed during regimen B approximated the normal postabsorptive state and were stable throughout the infusion period. The results of this study suggest that exogenous fat should be administered as a continuous infusion.