Limited data exist on the safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. A prospective observational study, including all adults aged 18 years and older with percentage predicted forced expiratory volume in 1 second (ppFEV) ⩽ 40 who initiated ETI from December 2019 to June 2021 in France, was conducted. PwCF were followed until August 8, 2022. ETI was initiated in 434 pwCF with a median ppFEV of 30 (interquartile range, 25-35), including 27 with severe cystic fibrosis liver disease and 183 with diabetes. PwCF were followed for a median of 587 (interquartile range, 396-728) days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was due mostly to lung transplantation ( = 5) or death ( = 4). Absolute increase in ppFEV by a mean of +14.2% (95% confidence interval, 13.1-15.4%) occurred at 1 month and persisted throughout the study. Increase in ppFEV in the youngest age quartile was almost twice that of the oldest quartile ( < 0.001); body mass index < 18.5 kg/m was found in 38.6% at initiation versus 11.3% at 12 months ( = 0.0001). Increases in serum concentrations of vitamins A and E, but not 25-hydroxy vitamin D, were observed. Significant reductions in the percentages of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, and inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of patients with diabetes. ETI is safe in pwCF and advanced lung disease, with multisystem pulmonary and extrapulmonary benefits.