Bone marrow-derived cells (BMDCs) can adopt an epithelial phenotype in the lung following bone marrow transplantation (BMT). This phenomenon has been assumed to result from the lung injury that occurs with myeloablative radiation. To date, no study has related the degree of epithelial chimerism following bone marrow transplantation to the lung damage induced by preconditioning for BMT. Such a goal is crucial to understanding the local host factors that promote the engraftment of BMDCs as lung epithelia. We undertook this aim by performing sex-mismatched bone marrow transplantation using a variety of preconditioning regimens and comparing measurements of lung injury (bronchoalveolar lavage [BAL] cell count, alveolar-capillary leak assayed by BAL protein levels, and terminal deoxynucleotidyl transferase dUTP nick-end labeling analysis on epithelial cells) with rigorous methods to quantify bone marrow-derived lung epithelia (costaining for epithelial and donor markers on tissue sections and isolated lung epithelia in recipient mice). We found that only at doses that induced lung injury could marrow derived lung epithelium be identified following BMT. With irradiation doses less than 1,000 centigray (cGy), there was little to no apparent injury to the lung, and there were no marrow-derived pneumocytes despite high levels of hematopoietic chimerism. In contrast, 4 days after either split or single-dose 1,000 cGy irradiation, nearly 15% of lung epithelia were apoptotic, and with this dose, marrow-derived type II pneumocytes (0.2%) were present at 28 days. These data indicate a critical relationship between lung injury and the phenotypic change from BMDCs to lung epithelial cells.