Organ and tissue damage caused by ionizing irradiation is directly related to volume irradiated, total dose and dose rate. The acute effects are in part mediated by cellular activation of early response genes, including those for transcriptional activators of genes for humoral cytokines. In the lung, as in other organs, recovery from the acute effects of ionizing irradiation does not always correlate with prevention of the critical late effects, including fibrosis, which contribute to organ failure. An interventional technique by which to protect normal organs from the late effects of irradiation has remained elusive. We now demonstrate that overexpression of a transgene for human manganese superoxide dismutase (MnSOD) delivered by plasmid-liposome, or adenovirus to the lungs of C57BL/6J or Nu/J mice, respectively, before irradiation exposure, decreases the late effects of whole lung irradiation (organizing alveolitis/fibrosis). These data provide a rational basis for the design of gene therapy approaches to organ protection from irradiation damage.