We determined whether normocapnic mechanical ventilation at high tidal volume (VT) and breathing frequency (f) during non-rapid-eye-movement (NREM) sleep would cause apnea. Seven normal sleeping subjects were placed on assist-control mechanical ventilation (i.e., subject initiates inspiration) and VT was gradually increased to 2.1 times eupneic VT (1.17 +/- 0.04 liters). This high VT was maintained for 5 min, the ventilator mode was switched to controlled mechanical ventilation, and f was increased gradually from 9.5 +/- 1.0 (during assist-control mechanical ventilation) to 14.0 +/- 0.7 breaths/min. Normocapnia (end-tidal PCO2 = 44 +/- 1.2 Torr) was maintained throughout the trials. Inspiratory effort was completely inhibited during the period of sustained high VT and f, and apnea occurred immediately after cessation of the passive mechanical ventilation. The duration of the apnea preceding the first inspiratory effort was 20.3 +/- 2.3 s or 7.1 times the eupneic expiratory duration and 5 times the expiratory duration chosen by the subject during assist-control mechanical ventilation. We conclude that inhibition of inspiratory motor output occurs during and after normocapnic mechanical ventilation at high VT and f during NREM sleep. These neuromechanical inhibitory effects may serve to initiate and prolong apnea.