End-stage renal disease (ESRD) is characterized by resting sympathetic overactivity. Baseline muscle sympathetic nerve activity (MSNA), which is governed by baroreflexes and chemoreflexes, is elevated in ESRD. Whether resting skin sympathetic nerve activity (SSNA), which is independent from baroreflex and chemoreflex control, is also elevated has never been reported in renal failure. The purpose of this study was to determine if sympathetic overactivity of ESRD is generalized to include the skin distribution. We measured sympathetic nerve activity to both muscle and skin using microneurography in 8 ESRD patients and 8 controls. MSNA was significantly (P=0.025) greater in ESRD (37.3 ± 3.6 bursts per minute) when compared with controls (23.1 ± 4.4 bursts per minute). However, SSNA was not elevated in ESRD (ESRD versus controls, 17.6 ± 2.2 versus 16.1 ± 1.7 bursts per minute, P=0.61). Similar results were obtained when MSNA was quantified as bursts/100 heart beats. We report the novel finding that although sympathetic activity directed to muscle is significantly elevated, activity directed to skin is not elevated in ESRD. The differential distribution of sympathetic outflow to the muscle versus skin in ESRD is similar to the pattern seen in other disease states characterized by sympathetic overactivity such as heart failure and obesity.