Background <p>Cystic fibrosis (CF) is a genetic disorder caused by variants in the CFTR gene. CFTR modulators, especially elexacaftor/tezacaftor/ivacaftor (ETI), have significantly improved CF care, but their effectiveness in children and adolescents with normal spirometry remains unexplored.</p> Methods <p>This prospective study included 103 individuals with CF under 18 years old, all with baseline percent predicted forced expiratory volume in one second (ppFEV₁) ≥ 90%. The outcomes assessed included sweat chloride concentration (SCC), body mass index (BMI), forced expiratory volume in one second (ppFEV₁), lung clearance index (LCI_2.5), P. <i>aeruginosa</i> colonization, and pulmonary exacerbation (PEX) rates over 12 months.</p> Results <p>Despite normal spirometry at baseline, 73.5% of participants exhibited abnormal LCI_2.5, indicating early lung disease. After ETI therapy, significant improvements were observed: SCC decreased by 56.0 mmol/L (95% CI: −60.6, −51.4) at 12 months; BMI increased by 0.26 standard deviation scores (95% CI: 0.18, 0.33); ppFEV₁ improved by 8.3 points (95% CI: 6.6, 10.1); and LCI_2.5 decreased by 1.68 units (95% CI: −2.00, −1.37). Additionally, the annual PEX rate declined from 2.75 to 1.50 (rate ratio: 0.54, 95% CI: 0.45–0.66).</p> Conclusions <p>ETI therapy provided substantial clinical benefits, supporting early intervention in pediatric patients with CF, even with preserved spirometry.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>This study explored the effects of ETI therapy in children and adolescents with CF and normal spirometry.</p> </ItemContent> <ItemContent> <p>Most showed early signs of lung disease based on LCI evaluation.</p> </ItemContent> <ItemContent> <p>ETI led to significant improvements in lung function and growth.</p> </ItemContent> <ItemContent> <p>Our findings stress the importance of early ETI intervention to optimize both growth and lung health in patients with CF.</p> </ItemContent> </UnorderedList></p>