The efficacy of prophylactic endotracheal administration of superoxide dismutase (SOD) was assessed in an animal model of acute lung injury induced by intratracheal endotoxin in neonatal piglets. Twenty-one anesthetized piglets were studied and underwent mechanical ventilation. The animals received recombinant human SOD (5 or 20 mg/kg intratracheally) 10 min before induction of acute lung injury with intratracheal endotoxin (20 mg/kg). The PaO2 values of the SOD-treated group remained higher than that of the control group until the end of the experiment. In contrast, the PaCO2 values remained lower. Lung compliance remained higher. Thiobarbituric acid-reactive substances and albumin levels in the broncho-alveolar lavage fluid were more significantly increased in controls. Histologic examination showed that the degrees of atelectasis and edema in the SOD treatment group were milder than those of the control group. Thus, the present findings suggest that prophylactic treatment with SOD may be, at least in part, effective for alleviating acute lung injury caused by endotoxins.