The ventilatory response to acute isocapnic hypoxia is prompt but is not maintained at its peak. Within 10 min, it begins to fall, and by 30 min has reached an approximately steady level, usually still above control. We used naloxone to test in four men the hypothesis that this fade is hypoxic depression mediated by endogenous opioid peptides, e.g, endorphins. Breath by breath minute ventilation was recorded during a hyperoxic control period (FIO2 = 0.3) to establish control alveolar PCO2. After 15 min. of isocapnic hypoxia (end-tidal PO2 = 45 Torr), naloxone injection (1.2 or 10 mg, iv) failed to alter the slow decrement of ventilation. Hypoxic ventilatory depression appears not to be mediated by endorphins in adults.