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For acute respiratory distress syndrome (ARDS), mechanical ventilation (MV) is a life-saving intervention without alternative; however, MV can cause ventilator-induced lung injury. Reactive oxygen species (ROS) play important roles in the pathogenesis of both ARDS and ventilator-induced lung injury. Lecithinized superoxide dismutase (PC-SOD) overcomes the limitations of superoxide dismutase such as low tissue affinity and low stability in plasma. In this study, we examined the effect of PC-SOD on tissue injury, edema, and inflammation in the lung and other organs of mice subjected to cecal ligation and puncture (CLP), LPS administration, or MV. The severity of the lung injury was assessed on the basis of vascular permeability, histopathologic evaluation, and lung mechanics. Intravenous PC-SOD administration (the first administered just before CLP) increased the survival rate and decreased vascular permeability in mice subjected to CLP. PC-SOD, but not dexamethasone or sivelestat sodium hydrate (sivelestat), suppressed CLP-induced kidney injury and systemic inflammation. PC-SOD also suppressed vascular permeability, tissue injury, and inflammation in the lung induced by LPS administration. Moreover, PC-SOD, but not dexamethasone or sivelestat, suppressed vascular permeability, edema, tissue injury, and mechanical alterations in the lung induced by MV. In vivo imaging analysis of ROS revealed that CLP, LPS administration, and MV increased the level of ROS and that this increase was suppressed by PC-SOD. The results of this study thus suggest that, on the basis of its ROS-reducing properties, intravenous administration of PC-SOD may be beneficial for patients at high risk of developing ARDS.