In cystic fibrosis (CF), extracellular lung matrix is progressively damaged, neutrophils invade the air spaces, and activated neutrophils may release large amounts of neutrophil elastase (NE). Although α 1-antiprotease (α 1-AP) binds and inactivates NE and is the major antielastase of the lower respiratory tract, antielastase defenses may be overwhelmed in CF, leading to progressive lung damage. To determine whether the ability of α 1-AP to neutralize NE is impaired in CF, we compared NE activity in bronchoalveolar lavage (BAL) fluid and human neutrophil elastase/α 1-antiprotease (NE/α 1-AP) complex in both BAL fluid and peripheral blood serum from patients with CF, normal volunteers, and patients with interstitial lung disease. We detected a considerable amount of NE activity in BAL fluid from all but one patient with CF but none in that from normal volunteers or from patients with interstitial lung disease. Although in interstitial lung disease there was a significant correlation between increased NE/α 1-AP complex in BAL or peripheral blood and the degree of neutrophil influx, NE/α 1-AP complex was disproportionately low in CF BAL compared with significantly elevated values in serum. These data suggest that in CF, α 1-AP-mediated defense against free NE in the lower respiratory tract is significantly impaired, and high levels of uncomplexed, enzymatically active, NE are present in CF respiratory secretions. To determine whether intravenously administered antipseudomonal antibiotic therapy for exacerbations of CF lung disease diminished the amount of free NE in respiratory secretions, we used BAL to investigate the effect of such therapy on neutrophils and NE in patients with CF colonized with pseudomonads. After 2 wk of intravenously administered antipseudomonal antibiotic therapy, free NE activity significantly diminished in BAL fluid (204±102 versus 89±46 nmol peptide hydrolyzed/min/ml BAL fluid; p= 0.02). Serum NE/α 1-AP complex also declined significantly in convalescent specimens (393±58 versus 183±24 µg/L; p= 0.0006) and approached levels near those of normal volunteer subjects (116±10 µg/L), although convalescent levels were still significantly increased above levels for normal volunteers (p= 0.04). Intensive antibiotic therapy diminished free NE in BAL fluid, but a considerable amount of NE activity remained in lower respiratory tract secretions after such therapy. Our data show that although antibiotics are of some benefit in reducing specific markers of pulmonary inflammation in CF, other therapies such as the administration of antiproteases also may prove useful in treating patients with CF by modulating progressive, protease-mediated lung damage.