Objective: Limited data exist concerning the role of inhaled hypertonic saline (HS) in decreasing pulmonary exacerbations in cystic fibrosis (CF), especially as more advanced stages of CF lung disease were excluded in prior studies. Herein we retrospectively determined the efficacy of inhaled HS in reducing CF pulmonary exacerbations when stratified according to the severity of CF lung disease. Stratification was based on the framework of the Pulmonary Therapeutics Committee’s published gradation of obstructive lung physiology in CF, i.e., mild (FEV1 > 70%), moderate (FEV1 40-70%) and severe (FEV1 < 40%) lung disease, respectively. Design: A retrospective review of the Port CF® database over a 3-year period performed at an academic CF care center. Results: 340 pulmonary exacerbations were identified; inhaled HS was being used in 99 of these cases. Univariate analysis demonstrated a significant reduction in pulmonary exacerbations only in mild obstruction (OR=0.09, CI 0.01-0.81, p=0.012); however, multivariate logistic regression that adjusted for confounding variables showed a reduction in pulmonary exacerbations across the entire spectrum of obstructive lung disease when using inhaled HS i.e., mild obstructive CF lung disease (OR=0.17, CI 0.05-0.58, p=0.004), moderate obstructive CF lung disease (OR=0.39, CI 0.16-0.93, p=0.034), as well as severe obstructive CF lung disease (OR=0.02, CI 0.001-0.45, p=0.015). Moreover, inhaled HS appeared reasonably well tolerated across all stages of lung disease severity, and was discontinued in only 7% of cases (n=4) with severe lung disease. Conclusion: In this study, inhaled HS appeared to reduce pulmonary exacerbations in CF lung disease at all stages of obstruction. This underscores the importance of therapeutic inhaled HS in CF lung disease, regardless of severity of lung obstruction.