The ventilatory response to hypercapnic progressive hypoxia and the breathing pattern during steady-state hypercapnic hypoxia were compared before and after intravenous infusion of 3 mg of naloxone in a relatively large number of healthy adults (n = 21). In addition, the withdrawal response from hypercapnic hypoxia (modified transient O₂ test) was measured to investigate the possible role of endogenous opioids in the peripheral chemoreceptors. The average ventilatory response (Δe/ΔSa_O2) increased significantly from 0.51 ± SD 0.26 to 0.65 ± 0.42 L/min/% (p < 0.05) after naloxone infusion, whereas there were no significant changes between two tests with normal saline in the control study (n = 7). Because there was considerable interindividual variation in the response to naloxone administration, we selected “high respondent” (n = 8) who showed larger increases with naloxone than the upper limit of the 95% confidence interval for the change with the second saline in the control study. They showed greater Δe/ΔSa_O2 (p < 0.01), respiratory frequency (p < 0.01), and mean inspiratory flow (p < 0.01) during hypercapnic hypoxia before naloxone infusion than did the other subjects. There was no significant change in the withdrawal response before and after naloxone infusion, even in such high responders. We conclude that endogenous opioids participate in the control of breathing in normal adults during hypercapnic hypoxia. This may be particularly true for those subjects who exhibit greater chemosensitivity to hypercapnic hypoxia. Endogenous opioids appear to act centrally rather than peripherally.