<jats:p> Patients with end-stage renal disease (ESRD) have decreased exercise capacity and exercise intolerance that contribute to cardiovascular risk. One potential mechanism underlying exercise intolerance in ESRD is impaired ability to oppose sympathetically mediated vasoconstriction within exercising skeletal muscle (i.e., functional sympatholysis, FS). We hypothesized that ESRD patients have impaired FS compared with healthy (CON) and hypertensive (HTN) controls and that impaired FS is related to circulating levels of the uremic toxin asymmetric dimethyl arginine (ADMA), an endogenous nitric oxide synthase inhibitor. Near-infrared spectroscopy-derived oxygen tissue saturation index (TSI) of the forearm muscle was measured continuously in 33 participants (9 CON, 14 HTN, 10 ESRD) at rest and during low-dose (−20 mmHg) lower body negative pressure (LBNP), moderate rhythmic handgrip exercise, and LBNP with concomitant handgrip exercise (LBNP+handgrip). Resting muscle TSI was lower in ESRD than in CON and HTN groups (CON = 67.8 ± 1.9%, HTN = 67.2 ± 1.1%, ESRD = 62.7 ± 1.5%, P = 0.03). Whereas CON and HTN groups had an attenuation in sympathetically mediated reduction in TSI during LBNP + handgrip compared with LBNP alone ( P ≤ 0.05), this response was not present in ESRD ( P = 0.71), suggesting impaired FS. There was no difference in plasma [ADMA] between groups (CON = 0.47 ± 0.05 µmol/l, HTN = 0.42 ± 0.06 µmol/l, ESRD = 0.63 ± 0.14 µmol/l, P = 0.106) and no correlation between plasma [ADMA] and resting muscle TSI ( P = 0.84) or FS ( P = 0.75). Collectively, these findings suggest that ESRD patients have lower muscle perfusion at rest and impaired FS but that these derangements are not related to circulating [ADMA]. </jats:p>