Introduction: There is an increasing interest in biphasic positive airway pressure with spontaneous breathing (BIPAP+SB_mean), which is a combination of time-cycled controlled breaths at two levels of continuous positive airway pressure (BIPAP+SB_controlled) and non-assisted spontaneous breathing (BIPAP+SB_spont), in the early phase of acute lung injury (ALI). However, pressure support ventilation (PSV) remains the most commonly used mode of assisted ventilation. To date, the effects of BIPAP+SB_mean and PSV on regional lung aeration and ventilation during ALI are only poorly defined.Methods: In 10 anesthetized juvenile pigs, ALI was induced by surfactant depletion. BIPAP+SB_mean and PSV were performed in a random sequence (1 h each) at comparable mean airway pressures and minute volumes. Gas exchange, hemodynamics, and inspiratory effort were determined and dynamic computed tomography scans obtained. Aeration and ventilation were calculated in four zones along the ventral-dorsal axis at lung apex, hilum and base.Results: Compared to PSV, BIPAP+SB_mean resulted in: 1) lower mean tidal volume, comparable oxygenation and hemodynamics, and increased PaCO₂ and inspiratory effort; 2) less nonaerated areas at end-expiration; 3) decreased tidal hyperaeration and re-aeration; 4) similar distributions of ventilation. During BIPAP+SB_mean: i) BIPAP+SB_spont had lower tidal volumes and higher rates than BIPAP+SB_controlled; ii) BIPAP+SB_spont and BIPAP+SB_controlled had similar distributions of ventilation and aeration; iii) BIPAP+SB_controlled resulted in increased tidal re-aeration and hyperareation, compared to PSV. BIPAP+SB_spont showed an opposite pattern.Conclusions: In this model of ALI, the reduction of tidal re-aeration and hyperaeration during BIPAP+SB_mean compared to PSV is not due to decreased nonaerated areas at end-expiration or different distribution of ventilation, but to lower tidal volumes during BIPAP+SB_spont. The ratio between spontaneous to controlled breaths seems to play a pivotal role in reducing tidal re-aeration and hyperaeration during BIPAP+SB_mean.