To determine whether sleep is necessary for the peripheral sympathetic nervous system response to exercise, we compared eight subjects' sympathoadrenal responses to treadmill walking at a constant exercise rate eliciting a heart rate around 160 beats X min-1 after normal sleep with those measured after a 50-h sleepless period. We found that sleeplessness left the sympathetic response to exercise intact. After 12 min of exercise, heart rate and plasma norepinephrine, epinephrine, and dopamine levels were similar in both situations. In addition, we could find no other alterations in the physiological response to exercise after sleep loss, and minute ventilation, oxygen uptake, blood lactate levels, and rectal and skin temperatures were identical in the two conditions. Nevertheless, despite both unaltered physiological responses to exercise and doubled monetary incentives to perform, sleep loss reduced time to exhaustion by 20% (P less than 0.01). We concluded that sleep loss does not diminish the peripheral sympathetic nervous system response to exercise, although it reduces exercise tolerance through mechanisms that are unexplained as yet.