Morphine reduces ventilation (VE) in exercising man. The mechanism of this ventilatory depression remains unclear. Recent evidence suggests that morphine may reduce exercise VE by simultaneously reducing exercise metabolic rate. We measured exercise VE in six normal subjects after intravenous injection of either saline or 0.1 mg/kg morphine sulfate. During treadmill walks requiring 1/3 and 2/3 of the maximal oxygen uptake, morphine reduced VE (P < 0.05), while it left metabolic rate unchanged. Morphine treatment elevated end-tidal PCO2 at both work levels (P < 0.05). Lower VE and higher PETCO2 in exercise after morphine persisted after elevation of alveolar PO2 to 200 torr. Thus, morphine left unchanged the contribution of the hypoxic chemoreflex to normoxic exercise VE. In addition, morphine failed to alter the ventilatory responses to hypercapnia measured at each exercise level. These results suggest that analgesic dosages of morphine reduce the ventilatory response to exercise through a mechanism other than alterations in metabolic rate or chemical ventilatory responses.