High levels of active neutrophil elastase (HNE) are present in the respiratory secretions of patients with cystic fibrosis (CF). We hypothesized that aerosolized Prolastin (alpha(1)-protease inhibitor or alpha(1)PI, purified from human blood) could suppress airway neutrophil inflammation and accelerate bacterial clearance from the lung in a model of chronic Pseudomonas aeruginosa lung infection. Because human alpha(1)PI effectively inhibits rat as well as human neutrophil elastase (NE) activity in vitro, we choose to test this hypothesis using a rat agar bead model of chronic P. aeruginosa lung infection. In this model, aerosolized Prolastin significantly decreased elastase activity (p < 0.01), lung neutrophil counts (p < 0.01), and bacterial colony counts (p < 0.01). Prolastin had no direct bactericidal effect on P. aeruginosa in vitro. Lung tissue histopathology revealed a marked decrease in lung inflammation in animals treated with Prolastin. These studies indicate that Prolastin can significantly decrease the elastase burden in the chronically infected lung. In addition, not only does Prolastin suppress lung inflammation, but it also markedly decreases P. aeruginosa density in a rat model of chronic P. aeruginosa lung infection. These data suggest that aerosolized alpha(1)PI may represent a useful nonantibiotic adjunct in the treatment and control of infection and inflammation associated with CF lung disease.