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Background: The combination of the CFTR corrector Lumacaftor (LUM) and potentiator Ivacaftor (IVA) has been labelled in France since 2015 for F508del homozygote cystic fibrosis (CF) patients over 12 years. Aims: Main: to compare the changes in ppFEV1 2 years before and after initiation of LUM/IVA treatment. Secondary: to assess (i) the evolution of clinical (weight, height, BMI, pulmonary exacerbations, antibiotic use), biological (sweat chloride concentration) and radiological parameters; (ii) to identify parameters associated with response to treatment; (iii) to assess the tolerance to treatment. Methods: In this tri-centre non-interventional observational cohort study, children (12-18 years old) were assessed prospectively during the two years of therapy, and retrospectively during the two years preceding treatment. Data collected and analysed for the study were exclusively extracted from the patients' medical electronic system. Findings: Forty adolescents aged 12.0 to 17.4 years at LUM/IVA initiation were included. Regarding ppFEV1, a decrease was present during the two years prior to treatment, followed by a significant increase after LUM/IVA initiation, becoming significant after 2 years of treatment. LUM/IVA significantly improved the BMI Z-score and sweat chloride concentration. By contrast, there was no significant change in exacerbation rates, antibiotic use or CT-scan scores. Age at LUM/IVA initiation was lower in good responders and was associated with greater ppFEV1 change during the 2 years of treatment. LUM/IVA was well tolerated. Interpretation: In F508del homozygote adolescents, real-life long-term LUM/IVA improves the ppFEV1 trajectory (in particular if introduced early), nutritional status and sweat chloride concentration but not exacerbation rates or radiological scores. LUM/IVA was generally well tolerated and safe. Funding Information: This study did not receive any specific funding. Declaration of Interests: SB, FG, CC, RE, FB, MF conduct clinical trials with Vertex pharmacological agents, on behalf of the European Cystic Fibrosis Society – Clinical Trials Network (ECFS-CTN) and within the scope of ECFS-CTN activities. The other authors have no conflicts of interest to declare. Ethics Approval Statement: The use of the data collected and analysed for the study were exclusively extracted from the patients' medical records (MUCODOMEOS, https://www.vaincrelamuco.org/2019/05/09/mucodomeos-un-logiciel-adapte-aux-besoins-des-crcm-2684) after having obtained their informed consent. In this context and according to the French law in force, the approval of an ethics committee was not required.