Radiotherapy can result in lung diseases pneumonitis or fibrosis dependent on patient susceptibility. Herein we used inbred and genetically altered mice to investigate whether the tissue adaptive immune response to radiation injury influences the development of radiation-induced lung disease. Six inbred mouse strains were exposed to 18 Gy whole thorax irradiation and upon respiratory distress strains prone to pneumonitis with fibrosis presented an increased pulmonary frequency of Thelper (Th)17 cells which was not evident in strains prone solely to pneumonitis. The contribution of Th17 cells to fibrosis development was supported as the known enhanced fibrosis of toll-like receptor 2&4 deficient mice, compared to C57BL/6J mice, occurred with earlier onset neutrophilia, and with increased levels of pulmonary Th17, but not Th1, cells following irradiation. Irradiated Il17-/- mice lacked Th17 cells, and were spared both fibrosis and pneumonitis, as they survived to the end of the experiment with a significantly increased pulmonary Th1 cell frequency, only. Interferon-γ-/- mice, deficient in Th1 cells, developed a significantly enhanced fibrosis response compared to that of C57BL/6J mice. The tissue adaptive immune response influences the pulmonary disease response to radiotherapy, as an increased Th17 cell frequency enhanced and a Th1 response spared, fibrosis in mice.