To investigate the physiologic effects of proportional assist ventilation (PAV) in difficult-to-wean, mechanically ventilated patients with advanced COPD, we measured in eight ICU patients the breathing pattern, neuromuscular drive (P0.1), lung mechanics, and inspiratory muscle effort (PTPdi and PTPpl) during both spontaneous breathing (SB) and ventilatory support with PAV, CPAP, and CPAP + PAV (in random sequence). PAV (volume assist [VA] and flow assist [FA]) was set as follows: dynamic lung elastance and inspiratory pulmonary resistance were measured during SB; then VA and FA were set to counterbalance the elastic and resistive loads exceeding the normal values, respectively, the inspiratory muscles bearing a normal elastic and resistive workload. CPAP was set close to dynamic intrinsic PEEP (8.3 +/- 3.4 cm H2O). We found significant reductions in P0.1 and PTPdi during both CPAP (-45 and -37%, respectively) and PAV (-50 and -48%, respectively). However, only the combination of PAV and CPAP brought P0.1 (1.69 +/- 0.97 cm H2O) and PTPdi (100 +/- 68 cm H2O. s) within normal values, and ameliorated the breathing pattern compared with SB (tidal volume: 0.69 +/- 0.33 versus 0.33 +/- 0.14 L; breathing frequency, 14.6 +/- 4.6 versus 21.0 +/- 6.5 breaths/min, respectively), without generating ineffective inspiratory efforts. We conclude that in difficult-to-wean COPD patients, (1) PAV improves ventilation and reduces both P0.1 and inspiratory muscle effort; (2) the combination of PAV and CPAP can unload the inspiratory muscles to values close to those found in normal subjects.