Background In patients with cystic fibrosis (CF), pulmonary structures with high MRI T2 signal intensity relate to inflammatory changes in the lung and bronchi. These areas of pathologic abnormalities can serve as imaging biomarkers. The feasibility of automated quantification is unknown. Purpose To quantify the MRI T2 high-signal-intensity lung volume and T2-weighted volume-intensity product (VIP) by using a black-blood T2-weighted radial fast spin-echo sequence in participants with CF. Materials and Methods Healthy individuals and study participants with CF were prospectively enrolled between January 2017 and November 2017. All participants underwent a lung MRI protocol including T2-weighted radial fast spin-echo sequence. Participants with CF also underwent pulmonary function tests the same day. Participants with CF exacerbation underwent repeat MRI after their treatment with antibiotics. Two observers supervised automated quantification of T2-weighted high-signal-intensity volume (HSV) and T2-weighted VIP independently, and the average score was chosen as consensus. Statistical analysis used the Mann-Whitney test for comparison of medians, correlations used the Spearman test, comparison of paired medians used the Wilcoxon signed rank test, and reproducibility was evaluated by using intraclass correlation coefficient. Results In 10 healthy study participants (median age, 21 years [age range, 18-27 years]; six men) and 12 participants with CF (median age, 18 years [age range, 9-40 years]; eight men), T2-weighted HSV was equal to 0% and 4.1% (range, 0.1%-17%), respectively, and T2-weighted VIP was equal to 0 msec and 303 msec (range, 39-1012 msec), respectively (P < .001). In participants with CF, T2-weighted HSV or T2-weighted VIP were associated with forced expiratory volume in 1 second percentage predicted (ρ = -0.88 and ρ = -0.94, respectively; P < .001). In six participants with CF exacerbation and follow-up after treatment, a decrease in both T2-weighted HSV and T2-weighted VIP was observed (P = .03). The intra- and interobserver reproducibility of MRI were good (intraclass correlation coefficients, >0.99 and >0.99, respectively). Conclusion In patients with cystic fibrosis (CF), automated quantification of lung MRI high-signal-intensity volume was reproducible and correlated with pulmonary function testing severity, and it improved after treatment for CF exacerbation. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Revel and Chassagnon in this issue.