To examine the effects of sodium intake on insulin sensitivity, we performed euglycemic insulin clamp studies (40 mU.m-2.min-1) in eight healthy normotensive nondiabetic white males (age = 36 +/- 5 yr; wt = 66 +/- 3 kg) after 5 days on high (200 meq/day)- and low (10 meq/day)-sodium diets administered in random order. High sodium intake was associated with significantly greater urinary sodium excretion (160 +/- 7 vs. 8 +/- 2 meq/day; P < 0.0001), suppression of plasma aldosterone (7 +/- 3 vs. 38 +/- 6 ng/dl; P < 0.001) and renin (1.5 +/- 0.2 vs. 6.0 +/- 0.9 ng.ml-1.h-1; P < 0.005) levels, but no change in blood pressure (116 +/- 3/63 +/- 2 vs. 114 +/- 3/64 +/- 2 mmHg; P = not significant). The rate of glucose infusion during the clamp was significantly reduced during the high- vs. low-sodium diet (279 +/- 19 vs. 334 +/- 24 mg.m-2.min-1; P < 0.01). This impairment in insulin sensitivity was not related to changes in serum potassium, epinephrine, norepinephrine, cortisol, or growth hormone but was highly correlated with an increment in circulating free fatty acid levels during high sodium intake (r = 0.82, P < 0.05). These data suggest that 1) high sodium intake may exacerbate insulin resistance by increasing circulating free fatty acids, and 2) differences in sodium intake may influence measures of insulin sensitivity in other disease states.