Background <p>Phase-resolved functional lung (PREFUL) MRI offers a more accessible alternative to hyperpolarized ¹²⁹Xe MRI (Xe-MRI) for monitoring treatment response in pediatric cystic fibrosis (CF), but longitudinal comparisons are limited.</p> Objective <p>To assess longitudinal lung function changes following elexacaftor/tezacaftor/ivacaftor (ETI) treatment initiation in CF children using PREFUL MRI, in comparison with Xe-MRI and pulmonary function tests (PFTs).</p> Materials and methods <p>PREFUL MRI, Xe-MRI, and PFTs were performed in 14 CF patients (median [IQR] age 15 [14–16.5] years old) at baseline and 1&#xa0;month, 6&#xa0;months, 12&#xa0;months, and 24&#xa0;months following initiation of ETI treatment. Ventilation and defect percentage (VDP) was derived from PREFUL MRI (regional ventilation VDP, VDP_RVent; regional-flow volume loop cross-correlation VDP, VDP_CC; and the combination of VDP_RVent and VDP_CC, VDP_combined) and Xe-MRI (VDP_Xe) maps. Perfusion defect percentage (QDP) was derived from normalized perfusion maps and, with VDP_combined, determined the percentage of healthy ventilation-perfusion matching (VQM). Significance of 1-month treatment changes was determined using the Wilcoxon-signed rank test and was correlated between metrics using Spearman ranked correlation.</p> Results <p>All PREFUL measures significantly improved (<i>P</i> &lt; 0.01) 1-month post-treatment in agreement with changes in Xe-MRI VDP and PFTs (<i>P</i> &lt; 0.03). The absolute change in VDP_CC and VDP_combined significantly correlated with VDP_Xe (<i>r</i> ≥ 0.62, <i>P</i> &lt; 0.02), unlike VDP_RVent (<i>P</i> = 0.35). The change in QDP did not correlate with any metric (<i>P</i> &gt; 0.10). PREFUL MRI and Xe-MRI measures showed minimal changes 1 to 24&#xa0;months post-treatment (median changes = -2.3% to 1.4%), in agreement with PFTs.</p> Conclusion <p>PREFUL MRI detects longitudinal treatment-related changes in pulmonary ventilation and perfusion in CF children post ETI.</p> Graphical Abstract <p></p>