BackgroundFree‐breathing ¹H ventilation MRI shows promise but only single‐center validation has yet been performed against methods which directly image lung ventilation in patients with cystic fibrosis (CF).PurposeTo investigate the relationship between ¹²⁹Xe and ¹H ventilation images using data acquired at two centers.Study typeSequence comparison.PopulationCenter 1; 24 patients with CF (12 female) aged 9–47 years. Center 2; 7 patients with CF (6 female) aged 13–18 years, and 6 healthy controls (6 female) aged 21–31 years. Data were acquired in different patients at each center.Field Strength/Sequence1.5 T, 3D steady‐state free precession and 2D spoiled gradient echo.AssessmentSubjects were scanned with ¹²⁹Xe ventilation and ¹H free‐breathing MRI and performed pulmonary function tests. Ventilation defect percent (VDP) was calculated using linear binning and images were visually assessed by H.M., L.J.S., and G.J.C. (10, 5, and 8 years' experience).Statistical TestsCorrelations and linear regression analyses were performed between ¹²⁹Xe VDP, ¹H VDP, FEV₁, and LCI. Bland–Altman analysis of ¹²⁹Xe VDP and ¹H VDP was carried out. Differences in metrics were assessed using one‐way ANOVA or Kruskal–Wallis tests.Results¹²⁹Xe VDP and ¹H VDP correlated strongly with; each other (r = 0.84), FEV₁ z‐score (¹²⁹Xe VDP r = −0.83, ¹H VDP r = −0.80), and LCI (¹²⁹Xe VDP r = 0.91, ¹H VDP r = 0.82). Bland–Altman analysis of ¹²⁹Xe VDP and ¹H VDP from both centers had a bias of 0.07% and limits of agreement of −16.1% and 16.2%. Linear regression relationships of VDP with FEV₁ were not significantly different between ¹²⁹Xe and ¹H VDP (P = 0.08), while ¹²⁹Xe VDP had a stronger relationship with LCI than ¹H VDP.Data Conclusion¹H ventilation MRI shows large‐scale agreement with ¹²⁹Xe ventilation MRI in CF patients with established lung disease but may be less sensitive to subtle ventilation changes in patients with early‐stage lung disease.Evidence Level2Technical EfficacyStage 2