Objectives: We recently described how spontaneous effort during mechanical ventilation can cause "pendelluft," that is, displacement of gas from nondependent (more recruited) lung to dependent (less recruited) lung during early inspiration. Such transfer depends on the coexistence of more recruited (source) liquid-like lung regions together with less recruited (target) solid-like lung regions. Pendelluft may improve gas exchange, but because of tidal recruitment, it may also contribute to injury. We hypothesize that higher positive end-expiratory pressure levels decrease the propensity to pendelluft and that with lower positive end-expiratory pressure levels, pendelluft is associated with improved gas exchange but increased tidal recruitment. Design: Crossover design. Setting: University animal research laboratory. Subjects: Anesthetized landrace pigs. Interventions: Surfactant depletion was achieved by saline lavage in anesthetized pigs, and ventilator-induced lung injury was produced by ventilation with high tidal volume and low positive end-expiratory pressure. Ventilation was continued in each of four conditions: positive end-expiratory pressure (low or optimized positive end-expiratory pressure after recruitment) and spontaneous breathing (present or absent). Tidal recruitment was assessed using dynamic CT and regional ventilation/perfusion using electric impedance tomography. Esophageal pressure was measured using an esophageal balloon manometer. Measurements and Results: Among the four conditions, spontaneous breathing at low positive end-expiratory pressure not only caused the largest degree of pendelluft, which was associated with improved ventilation/perfusion matching and oxygenation, but also generated the greatest tidal recruitment. At low positive end-expiratory pressure, paralysis worsened oxygenation but reduced tidal recruitment. Optimized positive end-expiratory pressure decreased the magnitude of spontaneous efforts (measured by esophageal pressure) despite using less sedation, from -5.6 ± 1.3 to -2.0 ± 0.7 cm H 2 O, while concomitantly reducing pendelluft and tidal recruitment. No pendelluft was observed in the absence of spontaneous effort. Conclusions: Spontaneous effort at low positive end-expiratory pressure improved oxygenation but promoted tidal recruitment associated with pendelluft. Optimized positive end-expiratory pressure (set after lung recruitment) may reverse the harmful effects of spontaneous breathing by reducing inspiratory effort, pendelluft, and tidal recruitment.