Dietary L-arginine supplementation has been proposed to reverse endothelial dysfunction in such diverse pathophysiologic conditions as hypercholesterolemia, coronary heart disease, and some forms of animal hypertension. In particular, chronic oral administration of L-arginine prevented the blood pressure rise induced by sodium chloride loading in salt-sensitive rats. To investigate the effects of L-arginine-rich diets on blood pressure and metabolic and coagulation parameters we performed a single-blind, controlled, crossover dietary intervention in six healthy volunteers. The subjects (aged 39+/-4 years, body mass index [BMI] 26+/-1 kg/m2, mean +/- SEM) received, in random sequence, three different isocaloric diets, each for a period of 1 week (Diet 1: control; Diet 2: L-arginine enriched by natural foods; Diet 3: identical to Diet 1 plus oral L-arginine supplement). Sodium intake was set at a constant level (about 180 mmol/day) throughout the three study periods. A blood pressure decrease was observed with both L-arginine-rich diets (Diet 2 v 1, SBP: -6.2 mm Hg [95% CI: -0.5 to -11.8], DBP: -5.0 mm Hg [-2.8 to -7.2]; Diet 3 v 1, SBP: -6.2 mm Hg [-1.8 to -10.5], DBP: -6.8 mm Hg [-3.0 to -10.6]). A slight increase in creatinine clearance (P = .07) and a fall in fasting blood glucose (P = .008) occurred after Diet 3 and, to a lesser extent, after Diet 2. Serum total cholesterol (P = .06) and triglyceride (P = .009) decreased and HDL cholesterol increased (P = .04) after Diet 2, but not after Diet 3. These results indicate that a moderate increase in L-arginine significantly lowered blood pressure and affected renal function and carbohydrate metabolism in healthy volunteers.