Variable ventilation (VV), in which tidal volume (V_T) and breathing rate (f) are varied from breath to breath, has been shown to improve lung mechanics and blood oxygenation during acute lung injury in many species compared to conventional ventilation (CV), in which V_T and f are constant. Since during ventilation of mice with CV as well as VV, the lungs tend to collapse over time, the goal of this study was to develop a new VV mode (VV_N) with an optimized distribution of V_T to maximize recruitment. Groups of normal and HCl injured mice were ventilated for 1 hr with CV, original VV (VV_O), CV with periodic large breaths (CV_LB) and VV_N. The effects of ventilation modes on respiratory mechanics, airway pressure, blood oxygenation and interleukin (IL)-1 were assessed. During CV and VV_O, both normal and injured mice showed regional lung collapse with increased airway pressures and poor oxygenation. Ventilation with CV_LB and VV_N resulted in a stable dynamic equilibrium with significantly improved respiratory mechanics and oxygenation. Nevertheless, VV_N provided a consistently better physiological response. In injured mice, both VV_O and VV_N, but not CV_LB, were able to minimize the IL-1 related inflammatory response compared to CV. In conclusion, our results suggest that the application of larger V_T's than the single V_T currently used in clinical situations helps stabilize lung function. Additionally, variable stretch patterns delivered to the lung by VV can reduce the progression of lung injury due to ventilation in injured mice.