The aim of the present study was to investigate the effect of salt intake on insulin sensitivity and the relation between salt sensitivity and insulin sensitivity in genetically hypertension-prone individuals. Twenty-eight healthy subjects (13 men and 15 women) with a family history of hypertension were examined at baseline, after 1 week of salt restriction (10 mmol/d), and after 1 week of salt loading (240 mmol/d). Insulin sensitivity was measured with the hyperinsulinemic euglycemic clamp after the low- and high-salt diets. Salt sensitivity was defined as the difference in mean arterial blood pressure between the high-salt and the low-salt diets. There was no significant relationship between insulin sensitivity and salt sensitivity after either of the 2 diets. In the men, salt sensitivity was inversely related to plasma renin activity (r=-0.61, P=0.03) and plasma aldosterone (r=-0.74, P=0.004), whereas salt sensitivity in women was directly correlated with the salt-induced increase in body weight (r=0.68, P=0.005). In men, the high-salt diet induced a change in glucose disposal that was strongly correlated with the degree of salt sensitivity (r=0.83, P=0. 0004), plasma renin activity (r=-0.82, P=0.0006), and plasma aldosterone concentrations (r=-0.87, P=0.00009) (eg, the greater the salt sensitivity and the lower the activity of the renin-angiotensin-aldosterone system, the greater improvement in insulin sensitivity). No such relationships were observed in women. In conclusion, increased salt sensitivity and decreased activity of the renin-angiotensin-aldosterone system predict improved insulin sensitivity with high-salt intake compared with low-salt intake in men, suggesting an interaction among salt intake, salt sensitivity, the renin-angiotensin-aldosterone system, and insulin action.