Measurement of skin sympathetic nerve activity (SSNA) during isometric exercise has been previously limited to the arm. We hypothesized that isometric leg exercise because of greater muscle mass would elicit greater SSNA responses than arm exercise because of presumably greater central command and muscle mechanoreceptor activation. To compare the effect of isometric arm and leg exercise on SSNA and cutaneous end-organ responses, 10 subjects performed 2 min of isometric knee extension (IKE) and handgrip (IHG) at 30% maximal voluntary contraction followed by 2 min of postexercise muscle ischemia (PEMI) in a normothermic environment. SSNA was recorded from the peroneal nerve. Cutaneous vascular conductance (laser-Doppler flux/mean arterial pressure) and electrodermal activity were measured within the field of cutaneous afferent discharge. Heart rate and mean arterial pressure significantly increased 16±3 and 23±3 beats/min and 22±2 and 27±3mmHg from baseline during IHG and IKE, respectively. Heart rate and mean arterial pressure responses were significantly greater during IKE compared to IHG. SSNA increased significantly and comparably during IHG and IKE (52±20% and 50±13%, respectively). During PEMI, SSNA and heart rate returned to baseline, whereas mean arterial pressure remained significantly elevated (12±2 and 13±2 mmHg from baseline for IHG and IKE, respectively). Neither cutaneous vascular conductance nor electrodermal activity was significantly altered by either exercise trial or by PEMI. These results indicate that despite cardiovascular differences in response to IHG and IKE, SSNA responses are similar at the same exercise intensity. Therefore the finds suggest that relative effort and not muscle mass is the main determinant of exercise-induced SSNA responses in humans.