<h3>Purpose/Objective(s)</h3> To quantify radiation therapy (RT)-induced dose-dependent changes in regional lung function (including pulmonary gas exchange), and their association with changes in global lung function. <h3>Materials/Methods</h3> Ten patients receiving conventional thoracic RT for lung cancer underwent pre-RT and 3-month post-RT MRI using an established hyperpolarized <sup>129</sup>Xe technique to map lung function. Four patients underwent additional <sup>129</sup>Xe MRI at 6-months post-RT. During <sup>129</sup>Xe MRI, the xenon signal is measured in three pulmonary compartments: the lung airspaces (indicating ventilation), the alveolar barrier (indicating tissue uptake), and interacting with capillary red blood cells, RBC (indicating gas exchange). During the same MRI session, a thoracic <sup>1</sup>H MRI is acquired for deformable registration of <sup>129</sup>Xe functional maps to the planning CT. The pre- vs. post-RT changes in ventilation, barrier uptake, and RBC transfer were computed as a function of regional lung dose, excluding ventilation-defects and high dose-gradient areas. Least-squares regression was used to define the dose-dependence of lung voxels receiving between 5-50Gy. Per patient, changes in whole-lung average xenon-measured function (i.e., the sum of regional injuries) were compared to changes in two pulmonary function tests, forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), by calculating Pearson correlation. <h3>Results</h3> At 3-months post-RT, ventilation decreased by -0.26%/Gy (R<sup>2</sup>=0.90), barrier uptake increased by 0.76%/Gy (R<sup>2</sup>=0.92), and RBC transfer decreased by -0.67%/Gy (R<sup>2</sup>=0.78) compared to the pre-RT baseline examination. The 6-month post-RT data also demonstrated a strong correlation between local RT dose and an increase in barrier uptake, at a rate of 0.76%/Gy (R<sup>2</sup>=0.87), compared to baseline. A decrease in ventilation (-0.19%/Gy, R<sup>2</sup>=0.20) and an increase in RBC transfer (0.26%/Gy, R<sup>2</sup>=0.26) were also observed at 6-months, but correlation with RT dose was poor. Examining per-patient pulmonary function 3-months after RT, moderate correlation was observed between the increase in whole-lung average barrier uptake and decreases in FVC (ρ=0.56, P=0.15) and DLCO (ρ=0.52, P=0.18), and between the increase in average RBC transfer and decrease in FVC (ρ=0.52, P=0.19). No correlation was observed between changes in whole-lung average ventilation and PFTs. <h3>Conclusion</h3> Hyperpolarized <sup>129</sup>Xe MRI was able to detect and quantify RT-induced dose-dependent changes in regional lung function, including pulmonary gas exchange. Additional work is needed to better define the role of <sup>129</sup>Xe MRI-based functional lung imaging to understand and predict RT-associated lung injury.