Central apneas occur after cessation of mechanical ventilation despite normocapnic conditions. We asked whether this was due to ventilator-induced increases in respiratory rate or VT. Accordingly, we compared the effects of increased VT (135 to 220% of eupneic VT) with and without increased respiratory rate, using controlled and assist control mechanical ventilation, respectively, upon transdiaphragmatic pressure in sleeping humans. Increasing ventilator frequency +1 per minute and VT to 165-200% of baseline eupnea eliminated transdiaphragmatic pressure during controlled mechanical ventilation and prolonged expiratory time (two to four times control) after mechanical ventilation. During and after assist control mechanical ventilation at 135-220% of eupneic VT, transdiaphragmatic pressure was reduced in proportion to the increase in ventilator volume. However, every ventilator cycle was triggered by an active inspiration, and immediately after mechanical ventilation, expiratory time during spontaneous breathing was prolonged less than 20% of that observed after controlled mechanical ventilation at similar VT. We conclude that both increased frequency and VT during mechanical ventilation significantly inhibited respiratory motor output via nonchemical mechanisms. Controlled mechanical ventilation at increased frequency plus moderate elevations in VT reset respiratory rhythm and inhibited respiratory motor output to a much greater extent than did increased VT alone.