Fludrocortisone reduces plasma norepinephrine in healthy humans, but forearm vascular and pressor responses to norepinephrine are potentiated. The effects of fludrocortisone on sympathetic nerve activity in healthy humans are not known. To investigate these effects we evaluated muscle sympathetic nerve activity, heart rate, and arterial pressure in 11 healthy volunteers during three protocols: (1) before and on day 7 of fludrocortisone (0.4 mg/d) treatment with ad libitum diet (n=6); (2) before and on day 7 of fludrocortisone (0.4 mg/d) or placebo with a 150 mmol/24 h (mEq/24 h) sodium diet (n=7); and (3) before and on day 2 of fludrocortisone (0.4 mg/d) or placebo with a 150 mmol/24 h (mEq/24 h) sodium diet (n=4). Placebo did not alter any parameter. Fludrocortisone produced expected mineralocorticoid effects on hormones and electrolytes: (1) plasma renin activity decreased (P<.05) on the seventh day of fludrocortisone treatment with both diets (1.4±0.3 to 0.8±0.2 ng/mL per hour with ad libitum diet and 3.7±1.2 to 1.3±0.7 ng/mL per hour with 150 mmol/24 h [mEq/24 h] sodium diet); (2) mean 24-hour urinary sodium excretion decreased during treatment (P<.05 day 4 versus day 0) and returned to baseline on day 7 (165±21, 137±31, and 174±30 mmol/24 h [mEq/24 h] with ad libitum diet and 132±18, 82±13, and 113±9 mmol/24 h [mEq/24 h] with 150 mmol/24 h [mEq/24 h] sodium diet on days 0, 4, and 7, respectively); and (3) after 2 days of treatment there was no change in plasma renin activity or 24-hour urinary sodium excretion. With ad libitum diet, fludrocortisone suppressed sympathetic nerve activity (18±4 to 6±3 bursts per minute, P<.05) and increased arterial pressure (90±4 to 96±3 mm Hg, P<.05) and body weight (77±3 to 79±3 kg, P<.05). With the 150 mmol/24 h (mEq/24 h) sodium diet, fludrocortisone also suppressed sympathetic nerve activity on day 2 (19±3 to 11 ±2 bursts per minute, P<.05) and day 7 (22±3 to 11±3 bursts per minute, P<.05). In contrast to the decrease in sympathetic nerve activity during fludrocortisone, arterial pressure and body weight did not change on either day 2 or 7, and plasma volume was increased only after 7 days of fludrocortisone (41±1 to 45±1 mL/kg, P<.05). This study demonstrates that fludrocortisone suppresses sympathetic nerve activity in humans and that this suppression may be related in part to factors other than increases in arterial pressure or plasma volume.