The extent to which sympathetic nerve activity restrains metabolic vasodilation in skeletal muscle remains unclear. We determined forearm blood flow (FBF, ultrasound/Doppler) and vascular conductance (FVC) responses to 10 min of ischemia (reactive hyperemic blood flow, RHBF) and 10 min of systemic hypoxia (FiO₂ 0.1) before and after regional sympathetic blockade with the -receptor antagonist phentolamine via Bier block in healthy humans. In a control group we performed sham Bier block with saline. Consistent with -receptor inhibition, post phentolamine, basal FVC (FBF/mean arterial pressure) increased (pre vs. post: 0.42 ± 0.05 vs. 1.03 ± 0.21 units; P < 0.01; n = 12) but did not change in the saline controls (pre vs. post: 0.56 ± 0.14 vs. 0.53 ± 0.08 units; P = NS; n = 5). Post phentolamine, total RHBF (over 3 min) increased substantially (pre vs. post: 628 ± 75 vs. 826 ± 92 ml/min, P < 0.01) but did not change in the controls (pre vs. post: 618 ± 66 vs. 661 ± 35 ml/min, P = NS). In all conditions, compared to peak RHBF, peak skin reactive hyperemia was markedly delayed. Furthermore, post phentolamine (pre vs. post: 0.43 ± 0.06 vs. 1.16 ± 0.17 units; P < 0.01; n = 8) but not post saline (pre vs. post: 0.93 ± 0.16 vs. 0.87 ± 0.19 ml/min; P = NS; n = 5), the FVC response to hypoxia (arterial O₂ saturation 77 ± 1%) was markedly enhanced. These data suggest that sympathetic vasoconstrictor nerve activity markedly restrains skeletal muscle vasodilation induced by local (forearm ischemia) and systemic (hypoxia) vasodilator stimuli.