Seven obese subjects were placed on a 400-kcal protein diet and on an isocaloric mixed diet (50 per cent protein and 50 per cent carbohydrate), three to 5 1/2 weeks for each diet. Despite twofold to fivefold increases in ketone levels in the blood and urine with the protein diet, net nitrogen balance was no different from that with the mixed diet (-2.1 +/- 0.9 vs. -2.6 +/- 0.4 g per day; mean +/- S.E.M.). However, net sodium loss with the protein diet (-382 +/- 117 mmol) was significantly greater than with the mixed diet (-25 +/- 105 mmol; P less than 0.02). Furthermore, maximal orthostatic decreases in systolic blood pressure with the protein diet (-28 +/- 3 mm Hg) were greater than with the mixed diet (-18 +/- 3 mm Hg; P less than 0.02) and were accompanied by symptoms of orthostatic hypotension in all patients. The protein diet (but not the mixed diet) also resulted in a 40 per cent decline in basal plasma levels of norepinephrine (P less than 0.01) and a failure of plasma norepinephrine to rise after two minutes of standing. We conclude that as compared with mixed diets, hypocaloric protein diets offer no advantage with respect to nitrogen metabolism but result in greater sodium depletion, a decrease in sympathetic-nervous-system activity, and the development of orthostatic hypotension.