Introduction:The combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been approved for treatment of cystic fibrosis patients (pwCF) homozygous and heterozygous for F508del. Aims and objectives:To assess the long-term effects of ETI therapy on clinical outcomes in severe pwCF. Methods: Lung function and pulmonary exacerbation were prospectively evaluated in a cohort of pwCF candidate to compassionate program of ETI.All the procedures were performed at baseline, 12 and 24 months after initiation of modulator therapy.The number of pulmonary exacerbations in the year before the study enrollment was collected from our records.Results:Thirty-four adult CF patients (17 females; mean age 36,1±10,58; BMI 20,43±2,88; 12 homozygous for F508del; FEV1 35,64±6,5 %predicted; FVC 60,52±12,56 %predicted) were recruited since 2019.All patients completed 2 years follow-up. A mean of 4,38±2,32 exacerbations per patient was reported in the preceding year, while the mean number of pulmonary exacerbations was 0,47±0,96 and 0,88±1,06 after 12 and 24 months of modulator therapy, respectively (p<0.0001 and p<0.0001).An improvement in FEV1 was observed at the first year (51,52±15,1 %predicted, p<0.0001) and was maintained at the second year (50,90±12,75 %predicted, p<0.0001). We observed an improvement from baseline of FVC both at the first and second year (78,35±17,28 %predicted, p<0.0001 and 77,81±15,10 %predicted, p<0.0001).Conclusions:Long-term combination therapy of ETI markedly impacts on clinical status in severe pwCF showing an improvement of lung function and pulmonary exacerbations rate.