To determine whether systemic administration of MnSOD-PL protected mice from the acute hematopoietic syndrome and delayed death after total-body irradiation (TBI), C57BL/ 6J mice were injected intravenously with 100 microl liposomes containing 100 microg of human MnSOD-transgene plasmid 24 h prior to irradiation with 9.5 Gy or 1.0 Gy. The dose of 9.5 Gy was lethal to 42% of irradiated control female mice and 74% of irradiated control male mice at 30 days, with bone marrow hypocellularity consistent with the hematopoietic syndrome. A statistically significant increase in survival was observed in MnSOD-PL-treated female mice out to 400 days and in male mice out to 340 days. The incidence of tumors was similar between surviving groups. Between 350 and 600 days, the outcome was similar for both MnSOD-PL-treated and control irradiated groups, consistent with aging, with no difference in gross or microscopic pathological evidence of tumors. Male and female mice receiving 1.0 Gy TBI showed radiation-induced life shortening after 120 days that was decreased by MnSOD-PL administration and that was not associated with an increase in rate of tumor-associated death. Therefore, systemic MnSOD-PL radioprotective gene therapy is not associated with a detectably higher incidence of late carcinogenesis.