Central apneas occur upon cessation of mechanical ventilation despite normocapnic conditions. We asked if this was due to ventilator-induced increases in respiratory rate or tidal volume. Accordingly, we compared the effects of increased tidal volume (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/min and tidal volume to 165-200% of baseline eupnea eliminated P_di during controlled mechanical ventilation and prolonged expiratory time (2-4 times control) following mechanical ventilation. During and following assist control mechanical ventilation at 135-220% of eupneic tidal volume, transdiaphragmatic pressure was reduced in proportion to the increase in ventilator volume. However, every ventilator cycle was triggered by an active inspiration and immediately following mechanical ventilation expiratory time during spontaneous breathing was prolonged less than 20% of that observed following controlled mechanical ventilation at similar VT. We conclude that both increased frequency and tidal volume during mechanical ventilation significantly inhibited respiratory motor output via non-chemical mechanisms. Controlled mechanical ventilation at increased frequency plus moderate elevations in tidal volume reset respiratory rhythm and inhibited respiratory motor output to a much greater extent than did increased VT alone.