This study was initiated to test the hypothesis that endogenous hypertriglyceridemia results from a defect in the ability of insulin to inhibit the release of very low-density lipoprotein-triglyceride (TG) from the liver. To accomplish this goal, plasma glucose, insulin, free fatty acid (FFA), and TG concentrations were compared in 12 healthy volunteers, in response to diets containing either 40% or 60% of total calories as carbohydrate (CHO). The protein content of the two diets was similar (15% of calories), and the fat content varied inversely with the amount of CHO (45% or 25%). The diets were consumed in random order, and measurements were made of plasma glucose, insulin, FFA, and TG concentrations at the end of each dietary period, fasting, and at hourly intervals following breakfast and lunch. The results indicated that the 60% CHO diet resulted in higher fasting plasma TG concentrations associated with higher day-long plasma insulin and TG concentrations, and lower FFA concentrations. These results do not support the view that hypertriglyceridemia is secondary to a failure of insulin to inhibit hepatic TG secretion.