The effectiveness of positive end-expiratory pressure (PEEP) relates directly to alveolar recruitment. We tested the hypothesis that active use of expiratory muscles during labored breathing impairs the ability of PEEP to increase end-expiratory lung volume. Eight healthy volunteers naive to the purposes of our study were exposed to targeted end-expiratory pressures of 0, 5, and 10 cm H2O during mechanical ventilation applied by mouthpiece and noseclips at three levels of ventilation: resting and two levels (moderate and high) of CO2 stimulation (10.9 +/- 0.4, 19.9 +/- 0.5 and 27.5 +/- 0.5 L/min, respectively). Inductive plethysmography demonstrated that end-expiratory lung volume rose by an average of 98 +/- 5 ml/cm H2O PEEP during quiet breathing but by much less during the two levels (moderate and high) of CO2 stimulation: 78 +/- 6 ml/cm H2O and 47 +/- 5 ml/cm H2O (p < 0.05). Hyperpnea also shifted the distribution of the recruited volume toward regions sampled by the rib cage band of the plethysmograph. Whatever advantage expiratory muscle activity may have for minimizing the workload of the inspiratory muscles, the cost may be reduced effectiveness of PEEP in increasing lung volume and improving oxygen exchange.