Rationale: Acute lung injury is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of acute lung injury. The fibrin-derived peptide B_15-42 was shown to preserve endothelial barriers, thereby preventing vascular leak. The potential therapeutic role of B_15-42 in acute lung injury was not addressed so far. Objectives: To investigate the therapeutic potential of B_15-42 in acute lung injury and secondary pneumonia induced by Pseudomonas aeruginosa. Methods: The effect of the fibrin derived peptide B_15-42 was studied in models of acute lung injury, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with Pseudomonas aeruginosa 24h after induction of aspiration pneumonitis and effects of B_15-42 on inflammation, bacterial clearance and survival were evaluated. Results: After LPS or acid inhalation proinflammatory cytokine levels, neutrophil influx as well as vascular leak was found diminished in mice treated with the peptide B_15-42. Acid aspiration rendered mice more susceptible to subsequent Pseudomonas aeruginosa infection, whereas mice that received B_15-42 during acid aspiration and were subsequently challenged with bacteria, displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. Conclusions: The fibrin-derived peptide B_15-42 exerted protective effects during acute lung injury, resulting in reduced vascular leak, diminished inflammation, and consecutively improved outcome during subsequent Pseudomonas aeruginosa pneumonia.