Background: The synthetic tripeptide feG (D-Phe-D-Glu-Gly) is a novel pharmacologic agent that decreases neutrophil recruitment, infi ltration, and activation in various animal models of infl ammatory disease. We aimed to investigate the effect of feG as both a preventive treatment when administered before acute lung injury and as a therapeutic treatment administered following initiation of acute lung injury. Methods: Lung injury was assessed following prophylactic or therapeutic intratracheal feG administration in a "two-hit" rodent model of acute pancreatitis plus intratracheal lipopolysaccharide. Results: Following both prophylactic and therapeutic feG administration, there were signifi cant improvements in arterial blood oxygenation and respiratory mechanics and decreased lung edema, BAL protein concentration, histologic tissue injury scores, BAL cell infi ltration, and lung myeloperoxidase activity. Most indices of lung damage were reduced to baseline control values. Conclusions: feG reduced leukocyte infi ltration, ameliorated the severity of infl ammatory damage, and restored lung function when administered either prophylactically or therapeutically in a twohit rat model of acute pancreatitis plus intratracheal lipopolysaccharide.