IntroductionXenon-129 (¹²⁹Xe) ventilation magnetic resonance imaging (MRI) is sensitive to detect early cystic fibrosis (CF) lung disease and response to treatment. ¹²⁹Xe-MRI could play a significant role in clinical trials and patient management. Here we present data on the repeatability of imaging measurements and their sensitivity to longitudinal change.Methods29 children and adults with CF and a range of disease severity were assessed twice, a median (interquartile range (IQR)) of 16.0 (14.4–19.5) months apart. Patients underwent ¹²⁹Xe-MRI, lung clearance index (LCI), body plethysmography and spirometry at both visits. 11 patients repeated ¹²⁹Xe-MRI in the same session to assess the within-visit repeatability. The ventilation defect percentage (VDP) was the primary metric calculated from ¹²⁹Xe-MRI.ResultsAt baseline, mean±sd age was 23.0±11.1 years and forced expiratory volume in 1 s (FEV₁) z-score was −2.2±2.0. Median (IQR) VDP was 9.5 (3.4–31.6)% and LCI was 9.0 (7.7–13.7). Within- and inter-visit repeatability of VDP was high. At 16 months there was no single trend of ¹²⁹Xe-MRI disease progression. Visible ¹²⁹Xe-MRI ventilation changes were common, which reflected changes in VDP. Based on the within-visit repeatability, a significant short-term change in VDP is >±1.6%. For longer-term follow-up, changes in VDP of up to ±7.7% can be expected, or ±4.1% for patients with normal FEV₁. No patient had a significant change in FEV₁; however, 59% had change in VDP >±1.6%. In patients with normal FEV₁, there were significant changes in ventilation and in VDP.Conclusions¹²⁹Xe-MRI is a highly effective method for assessing longitudinal lung disease in patients with CF. VDP has great potential as a sensitive clinical outcome measure of lung function and end-point for clinical trials.