Gastric aspiration is the major cause of acute lung injury (ALI) and acute respiratory distress syndrome. Aspiration-induced ALI is believed to be, at least in part, facilitated by neutrophil-derived mediators and toxic molecules. We conducted a prospective cohort study based on the hypothesis that sivelestat, a specific neutrophil elastase inhibitor, is effective for treating ALI following gastric aspiration. Forty-four ALI patients who showed evidence of aspiration were observed within 12 h before intensive care unit admission and who had been mechanically ventilated within 12 h after admission were included in this study. Lung injury score (LIS) and PAO2/FiO2 (P/F) ratio on day 7 were defined as the primary outcomes of the study. Twenty-three patients were assigned to the sivelestat group and 21 to the control group. In univariate analyses, the proportions of patients with LIS lower than 1.0 on day 7 and a P/F greater than 300 on day 7 were significantly higher in the sivelestat group than in the control group (60.9% vs. 26.3%, P = 0.03; 87.0% vs. 36.8%, P = 0.001). In the logistic regression model, the use of sivelestat was an independent predictor for LIS lower than 1.0 on day 7 (relative risk, 7.4; 95% confidence interval [CI], 1.51-36.48) and for a P/F ratio higher than 300 on day 7 (relative risk, 18.5; 95% CI, 2.72-126.46). In the Cox proportional hazards model, the use of sivelestat was associated with a lower cumulative proportion of patients who received mechanical ventilation during the initial 14 days (hazard ratio, 2.6; 95% CI, 1.17-5.55).