Abstract Introduction Sigh improves oxygenation and lung mechanics during pressure control ventilation (PCV) and pressure support ventilation (PSV) in patients with acute respiratory distress syndrome. However, so far, no study has evaluated the biological impact of sigh during PCV or PSV on the lung and distal organs in experimental pulmonary (p) and extrapulmonary (exp) mild acute lung injury (ALI). Methods In 48 Wistar rats, ALI was induced by Escherichia coli lipopolysaccharide either intratracheally (ALIp) or intraperitoneally (ALIexp). After 24 hours, animals were anesthetized and mechanically ventilated with PCV or PSV with a tidal volume of 6 mL/kg, FiO 2  = 0.4, and PEEP = 5 cmH 2 O for 1 hour. Both ventilator strategies were then randomly assigned to receive periodic sighs (10 sighs/hour, Sigh) or not (non-Sigh, NS). Ventilatory and mechanical parameters, arterial blood gases, lung histology, interleukin (IL)-1β, IL-6, caspase-3, and type III procollagen (PCIII) mRNA expression in lung tissue, and number of apoptotic cells in lung, liver, and kidney specimens were analyzed. Results In both ALI etiologies: (1) PCV-Sigh and PSV-Sigh reduced transpulmonary pressure, and (2) PSV-Sigh reduced the respiratory drive compared to PSV-NS. In ALIp: (1) PCV-Sigh and PSV-Sigh decreased alveolar collapse as well as IL-1β, IL-6, caspase-3, and PCIII expressions in lung tissue, (2) PCV-Sigh increased alveolar-capillary membrane and endothelial cell damage, and (3) abnormal myofibril with Z-disk edema was greater in PCV-NS than PSV-NS. In ALIexp: (1) PSV-Sigh reduced alveolar collapse, but led to damage to alveolar-capillary membrane, as well as type II epithelial and endothelial cells, (2) PCV-Sigh and PSV-Sigh increased IL-1β, IL-6, caspase-3, and PCIII expressions, and (3) PCV-Sigh increased the number of apoptotic cells in the lung compared to PCV-NS. Conclusions In these models of mild ALIp and ALIexp, sigh reduced alveolar collapse and transpulmonary pressures during both PCV and PSV; however, improved lung protection only during PSV in ALIp.