The response of respiratory motor output to CO2 in the hypocapnic range (< 36 Torr PCO2) in the absence of hypoxemia is not well characterized in awake normal humans. We induced hypocapnia with hyperoxia in 16 normal volunteers by placing them on a volume-cycled ventilator in the assist mode. Subjects were not aware of the purpose of the study. All subjects continued rhythmic breathing despite high tidal volumes and severe hypocapnia (approximately 25 Torr alveolar PCO2). Inspired CO2 fraction was increased in steps, and changes in respiratory motor output were quantitated from changes in airway pressure at constant volume and flow, changes in respiratory rate, and change in rate of decline in airway pressure before triggering (dP/dt). There was a significant increase in respiratory muscle pressure, but not in respiratory rate, from 26 to 36 Torr PCO2. The slope of the response increased gradually from 26 to 41 Torr PCO2. Respiratory rate significantly increased only above 36 Torr. We conclude that the response to PCO2 in the hypocapnic range is basically nonlinear with no clear CO2 threshold and the CO2 responsiveness extends well below eupneic CO2 levels.