Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators have been reported to improve lung function and reduce CF exacerbations. We aimed to investigate the efficacy of CFTR-modulators in CF-associated liver disease (CFLD) during long-term treatment. Longitudinal data were collected from genetically confirmed adult CF patients receiving CFTR-modulators. CFLD was diagnosed using conventional criteria combined with liver stiffness measurement (LSM). A total of 57 patients [56.1% male; median age at baseline (T0), 26 years (interquartile range [IQR], 23–35)] were included. Patients received lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor for a median of 43 months (range, 15–123) until last assessment (T2). The prevalence of CFLD decreased from 15 (26.3%) at T0 to 8 (14.0%) at T2 (p = 0.016), and no new cases of CFLD were observed. Median LSM decreased from 6.2 (IQR 4.9–8.0) to 5.0 kPa (IQR 4.1–6.2) in the overall cohort (p < 0.001) and from 10.2 (IQR 6.8–13) to 6.2 kPa (IQR 5.0–12.4) in the CFLD subgroup (p = 0.025). Mild, transient fluctuations in liver enzymes occurred in 26.3% of patients. In conclusion, adults with CF receiving long-term CFTR modulators, showed improvement of liver disease assessed by ultrasonography and transient elastography. At the last assessment, half of the patients no longer met the criteria for CFLD.