The importance of hypoxemia in determining sympathoexcitation during obstructive sleep apnea was examined by comparing changes in efferent sympathetic nerve activity (SNA) during spontaneous obstructive apneas with hypoxemia alone of similar magnitude and duration induced by 1-4 breaths of 100% nitrogen in six patients with obstructive sleep apnea and with spontaneous apneas while breathing 100% oxygen (apnea without hypoxemia) in three patients. In addition, eight control subjects were studied during induced hypoxemia. The magnitude of sympathoexcitation during spontaneous apneas (103 +/- 15%) was more than twice that observed during induced hypoxemia (47 +/- 14%) during episodes in which the nadir of oxygen desaturation (78 +/- 2 and 75 +/- 2%, respectively) and duration of hypoxemia (27 +/- 3 and 33 +/- 3 s, respectively) were the same (P > 0.20). Similarly, in three patients SNA increased 115% during normoxic spontaneous obstructive apneas, but increased only 43% during hyperoxic spontaneous obstructive apneas in which oxygen saturation did not decrease significantly. Sympathetic neural responses to induced hypoxemia in control subjects (17 +/- 7%) were significantly less than that of the sleep apnea patients. We conclude that hypoxemia contributes importantly, but is not the sole determinant of the sympathoexcitation provoked during episodes of obstructive sleep apnea.