Subsets of cancer survivors who have been subjected to thoracic irradiation face the prospect of developing pulmonary injury. Radiation-induced pulmonary fibrosis is an insidious injury that presents 6 to 24months after irradiation and continues to progress over a period of years. TGF-β and reactive oxygen species contribute significantly to the pathogenesis of this injury. The transcription factor NRF2 controls antioxidant gene expression and therefore regulates the cellular oxidant burden. This work demonstrates an additional paradigm for NRF2: suppression of TGF-β-mediated signaling, assessed by measuring expression of a surrogate TGF-β1 target gene (PAI-1) in lung fibroblasts. Thoracic irradiation of Nfe2l2^−/− mice resulted in rapid expression of PAI-1 and FSP-1 compared to irradiated wild-type mice. Examination of lung tissue 16weeks after thoracic irradiation of Nfe2l2^−/− mice revealed the presence of distended alveoli and decreased numbers of alveoli compared to wild-type mice. Suppression of NRF2 expression shortened life span in mice administered 16Gy to the thorax. Nfe2l2^+/− and Nfe2l2^−/− mice exhibited a mean life span of 176days compared to wild-type mice, which lived an average of 212days. These novel results identify NRF2 as a susceptibility factor for the development of late tissue injury.