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Background: Elexacaftor/tezacaftor/ivacaftor (ETI), which is approved for people with cystic fibrosis (pwCF) with a F508del variant, was further approved based on in vitro data in the USA for those carrying at least one of 177 rare CFTR (cystic fibrosis transmembrane conductance regulator) variants., Methods: PwCF, aged ≥6 years, carrying no F508del variant but with at least one of these 177 rare variants, were identified within the US Cystic Fibrosis Foundation Patient Registry (CFFPR) between 2020 and 2022. The evolution of forced expiratory volume in 1 s (FEV 1 ) percentage predicted and rates of pulmonary exacerbations were analysed over the first year following ETI initiation, using a linear regression with generalised estimating equations and a negative binomial model, respectively., Results: A total of 1791 individuals aged ≥6 years with rare CFTR variants were eligible for ETI, corresponding to 5.2% of CFFPR participants. 815 individuals (45.5%), of which 57.9% were already treated with another CFTR modulator, initiated ETI within the first 2 years following approval. Individuals with more severe respiratory disease were more likely to initiate ETI, whereas those previously treated with another CFTR modulator or those with no private insurance coverage had less ETI initiation. ETI initiation was associated with an increase in mean FEV 1 % pred by +3.39 (95% CI 2.14-4.64) and a decrease in the rates of pulmonary exacerbations (adjusted rate ratio 0.55, 95% CI 0.38-0.79). These effects were greater in individuals naïve of previous CFTR modulators., Conclusions: Extension of the ETI label to rare CFTR variants is associated with meaningful improvements in lung function and a marked reduction in pulmonary exacerbations., Competing Interests: Conflict of interest: E.A. Cromwell reports support for the present study from the Cystic Fibrosis Foundation. J.S. Ostrenga has nothing to disclose. D.B. Sanders reports support for the present study from the Cystic Fibrosis Foundation (CFF), grants from the CFF, consultancy fees from the CFF for roles on the Registry Committee, Data Safety Monitoring Board (DSMB) and Grant Review Committee, and participation on a DSMB or Advisory Board with the CFF. W. Morgan reports support for the present study from the Cystic Fibrosis Foundation (CFF) as a paid consultant for work on the CFF Registry Committee, covering a range of activities including papers, analyses and reviews of protocol/data requests; additionally, grants were received from the NIH/NHLBI for the ORBEX study (Site PI and Executive Committee) and the Tucson Children's Respiratory Study, from Boston Children's Hospital/Harvard for consultancy to the PARK study (NIH/NIAID), and from the CFF for Data Safety Monitoring Board (DSMB) infrastructure; consultancy fees were also received from the CFF for DSMB-related activities; payment for lectures was received from the American College of Chest Physicians for the 2022 Pediatric Pulmonology Board Prep Course; support for attending meetings was provided by the CFF for travel to the CFF DSMB meeting in April 2023; participation on a DSMB or Advisory Board includes serving as Chair of the CFF DSMB, chairing several DSMBs for CF clinical research trials and participation on the NIH/NHLBI PRIMERO Observational Study Monitoring Board. C. Castellani reports participation on a Data Safety Monitoring Board or Advisory Board with Vertex and Chiesi. R. Szczesniak reports payment or honoraria for lectures, presentations, manuscript writing or educational events from the Cystic Fibrosis Foundation (CFF) Patient Registry Committee; additionally, support for attending meetings and/or travel was provided by the CFF Patient Registry Committee. P-R. Burgel reports grants or contracts from GSK and Vertex, and consultancy fees from AstraZeneca, Chiesi, GSK, Insmed, MSD, Sanofi, Viatris, Vertex and Zambon., (Copyright ©The authors 2024.)