To examine whether achievable dietary changes influence insulin sensitivity, we performed euglycemic hyperinsulinemic glucose clamps in eight normal subjects who were prescribed high carbohydrate and high fat diets. The high carbohydrate diet was more than 50% (of energy intake) carbohydrate and less than 30% fat; the high fat diet was more than 45% fat (predominantly saturated) and less than 40% carbohydrate. The diets were consumed over consecutive 3-week periods in random sequence. The mean whole body glucose uptake during the glucose clamps was similar after the high carbohydrate (48.3 mumol/kg.min) and high fat diets (47.0 mumol/kg.min; P = 0.5; 95% confidence interval for the difference, -3.4 to 5.9 mumol/kg.min). Fasting blood glucose and serum insulin concentrations were also unchanged. In contrast, there were substantial effects on lipoprotein metabolism. During the high carbohydrate diet, fasting serum cholesterol decreased by 17% (P = 0.06), low density lipoprotein cholesterol decreased by 20% (P = 0.05), high density lipoprotein cholesterol decreased by 24% (P less than 0.005), and triglyceride increased by 33% (P = 0.06) compared with levels during the high fat diet. These results suggest that practically achievable high carbohydrate diets do not enhance insulin sensitivity in nondiabetic subjects and have net effects on lipoprotein metabolism that may be unfavorable.