OBJECTIVE: Recent interest has arisen in airway driving pressure (DPAW), the quotient of tidal volume (VT), and respiratory system compliance (CRS), which could serve as a direct and easily measured marker for ventilator-induced lung injury risk. We aimed to test the correspondence between DPAW and transpulmonary driving pressure (DPTP)-the quotient of VT and lung compliance (CL), in response to intra-abdominal hypertension and changes in positive end-expiratory pressure during different models of lung pathology. DESIGN: Well-controlled experimental setting that allowed reversible modification of chest wall compliance (CCW) in a variety of models of lung pathology. SETTING: Large animal laboratory of a university-affiliated hospital. SUBJECTS: Ten deeply anesthetized swine. INTERVENTIONS: Application of intra-abdominal pressures of 0 and 20 cm H2O at positive end-expiratory pressure of 1 and 10 cm H2O, under volume-controlled mechanical ventilation in the settings of normal lungs (baseline), unilateral whole-lung atelectasis, and unilateral and bilateral lung injuries caused by saline lavage. MEASUREMENTS AND MAIN RESULTS: Pulmonary mechanics including esophageal pressure and calculations of DPAW, DPTP, CRS, CL, and CCW. When compared with normal intra-abdominal pressures, intra-abdominal hypertension increased DPAW, during both "normal lung conditions" (p < 0.0001) and "unilateral atelectasis" (p = 0.0026). In contrast, DPTP remained virtually unaffected by changes in positive end-expiratory pressure or intra-abdominal pressures in both conditions. During unilateral lung injury, both DPAW and DPTP were increased by the presence of intra-abdominal hypertension (p < 0.0001 and p = 0.0222, respectively). During bilateral lung injury, intra-abdominal hypertension increased both DPAW (at positive end-expiratory pressure of 1 cm H2O, p < 0.0001; and at positive end-expiratory pressure of 10 cm H2O, p = 0.0091) and DPTP (at positive end-expiratory pressure of 1 cm H2O, p = 0.0510; and at positive end-expiratory pressure of 10 cm H2O, p = 0.0335). CONCLUSIONS: Our data indicate that DPAW is influenced by reductions in chest wall compliance and by underlying lung properties. As with other measures of pulmonary mechanics that are based on unmodified PAW, caution is advised in attempting to attribute hazard or safety to any specific absolute value of DPAW.