OBJECTIVE:To utilize real-time electrical impedance tomography to guide lung protective ventilation in an animal model of acute respiratory distress syndrome. DESIGN:Prospective animal study. SETTING:Animal research center. SUBJECTS:Twelve Yorkshire swine (15 kg). INTERVENTIONS:Lung injury was induced with saline lavage and augmented using large tidal volumes. The control group (n = 6) was ventilated using ARDSnet guidelines, and the electrical impedance tomography–guided group (n = 6) was ventilated using guidance with real-time electrical impedance tomography lung imaging. Regional electrical impedance tomography–derived compliance was used to maximize the recruitment of dependent lung and minimize overdistension of nondependent lung areas. Tidal volume was 6 mL/kg in both groups. Computed tomography was performed in a subset of animals to define the anatomic correlates of electrical impedance tomography imaging (n = 5). Interleukin-8 was quantified in serum and bronchoalveolar lavage samples. Sections of dependent and nondependent regions of the lung were fixed in formalin for histopathologic analysis. MEASUREMENTS AND MAIN RESULTS:Positive end-expiratory pressure levels were higher in the electrical impedance tomography–guided group (14.3 cm H2O vs. 8.6 cm H2O; p < 0.0001), whereas plateau pressures did not differ. Global respiratory system compliance was improved in the electrical impedance tomography–guided group (6.9 mL/cm H2O vs. 4.7 mL/cm H2O; p = 0.013). Regional electrical impedance tomography–derived compliance of the most dependent lung region was increased in the electrical impedance tomography group (1.78 mL/cm H2O vs. 0.99 mL/cm H2O; p = 0.001). Pao2/FIO2 ratio was higher and oxygenation index was lower in the electrical impedance tomography–guided group (Pao2/FIO2388 mm Hg vs. 113 mm Hg, p < 0.0001; oxygentation index, 6.4 vs. 15.7; p = 0.02) (all averages over the 6-hr time course). The presence of hyaline membranes (HM) and airway fibrin (AF) was significantly reduced in the electrical impedance tomography–guided group (HMEIT 42% samples vs. HMCONTROL 67% samples, p < 0.01; AFEIT 75% samples vs. AFCONTROL 100% samples, p < 0.01). Interleukin-8 level (bronchoalveolar lavage) did not differ between the groups. The upper and lower 95% limits of agreement between electrical impedance tomography and computed tomography were ± 16%. CONCLUSIONS:Electrical impedance tomography–guided ventilation resulted in improved respiratory mechanics, improved gas exchange, and reduced histologic evidence of ventilator-induced lung injury in an animal model. This is the first prospective use of electrical impedance tomography–derived variables to improve outcomes in the setting of acute lung injury.