BACKGROUND. Physiological hyperinsulinemia in lean human subjects stimulates sympathetic nerve activity and blood flow in skeletal muscle, but the underlying mechanism is unknown. Potential mechanisms include central neural or peripheral actions of insulin. Glucocorticoids may potentially interfere with both such actions and thereby may attenuate sympathoexcitatory and vasodilatory effects of insulin in skeletal muscle. METHODS AND RESULTS. To determine whether insulin-induced sympathetic activation and vasodilation are attenuated by dexamethasone, we measured muscle sympathetic nerve activity and muscle blood flow during euglycemic hyperinsulinemia before and after short-term administration of this pharmacological agent. Insulin concentrations, which normally doubled sympathetic activity and markedly increased blood flow, had no such stimulatory effect after short-term dexamethasone administration. In contrast, responses to two noninsulin sympathetic stimuli, the Valsalva maneuver and immersion of the hand in ice water, and the vasodilatory response to calf vascular occlusion were not altered by dexamethasone. CONCLUSIONS. These results demonstrate a dramatic impairment of insulin-induced sympathetic activation and vasodilation by dexamethasone in lean, healthy humans. This study suggests that dexamethasone administration to lean subjects may offer an experimental model to examine underlying mechanisms that regulate the interplay between cardiovascular, sympathetic, and metabolic effects of insulin.