Background: Multiple Breath washout (MBW) represents an important tool to detect early a possible pulmonary exacerbation especially in Cystic Fibrosis (CF) disease. Lung clearance index (LCI) is the most commonly reported multiple breath washout (MBW) index and in the last years was used as management measure for evaluation. Our aim was to analyze clinical utility of LCI index variability in pulmonary exacerbation in CF. Methods: A single-center study was conducted at CF Unit of Bambino Gesù Children’s Hospital among hospitalized > 3 years patients for pulmonary exacerbations and treated with antibiotic intravenous treatment for 14 days. MBW and spirometry were evaluated within 72 hours of admission to hospital and at the end of hospitalization. Descriptive analysis was conducted and correlations between quantitative variables were investigated. Results: Fifty-seven patients (M22/F35) with an average age 18.56 (± 8.54) years were enrolled. LCI 2.5 was significantly reduced at the end of antibiotic treatment in both pediatric and adult populations with an average improvement of -6% in 37/57 patients. 26/57 are stable in LCI values. A significant elevation of +7.30% was found for FEV1%. 4/57 (7.02 %) had a significant deterioration in LCI values at the end of IV antibiotic treatment. A positive good correlation among LCI 2.5 and Scond (rho= +0.615, p=0.000) and LCI 2.5 and Sacin (rho=+0.649, p=0.000) and a negative strong correlation between FEV1% and LCI 2.5 were found in post treatment period. A better increase of LCI 2.5 in < 18 years (-10.27% vs -4.57%) than adult was noticed. Conclusions: LCI may have a role in the routine clinical care of CF patients as a good tool to assess response to intravenous antibiotic therapy.