It has been shown in mechanically ventilated patients that pressure support (PS) unloads the respiratory muscles in a graded fashion depending on the PS level. The downregulation of respiratory muscles could be mediated through chemical or load-related reflex feedback. To test this hypothesis, 8 patients with acute lung injury mechanically ventilated on PS mode (baseline PS) were studied. In Protocol A, PS was randomly decreased or increased by at least 5 cmH2O for two breaths. During this time, which is shorter than circulation delay, only changes in load-related reflex feedback were operating. Sixty trials where PS increased (high PS) for two breaths and 62 trials where PS decreased (low PS), also for two breaths were analysed. Thereafter, the patients were assigned randomly to baseline, low or high PS and ventilated in each level for 30 min (Protocol B). The last 2 min of each period were analysed. Respiratory motor output was assessed by total pressure generated by the respiratory muscles (Pmus), computed from oesophageal pressure (Poes). In Protocol A, alteration in PS caused significant changes in tidal volume (VT) without any effect on Pmus waveform except for neural expiratory time (ntE). ntE increased significantly with increasing PS. In Protocol B, Pmus was significantly down-regulated with increasing PS. Carbon dioxide tension in arterial blood (Pa,CO2) measured at the end of each period increased with decreasing PS. There was not any further alteration in ntE beyond that observed in Protocol A. These results indicate that the effect of load-related reflex on respiratory motor output is limited to timing. The downregulation of pressure generated by the respiratory muscles with steady-state increase in pressure support is due to a slow feedback system, which is probably chemical in nature.