The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.