Exposure to high doses of ionizing radiation can lead to death, lifespan shortening, cataract formation, or carcinogenesis. There is currently no approved drug or therapy for the treatment of radiation injuries. Oxidative stress is a major determinant for radiation-induced tissue injuries. We propose a method that harnesses migration of mesenchymal stem cells (MSCs) to radiation injured tissues and adenovirus-mediated extracellular superoxide dismutase (ECSOD) gene therapy for oxidative stress.In a previous study, we demonstrated for the first time that intravenous administration of MSCs genetically modified to secrete ECSOD(ECSOD-MSCs) improved survival from 10% to 52% in irradiated mice (Abdel-Mageed et al., Blood, 113: 1201-1203, 2009). Here we present data showing that intravenous administration of ECSOD-MSCs extended lifespan, retarded cataract formation, and prevented carcinogenesis in irradiated mice. For the first stage of clinical proof-of-concept, we also present data showing that human MSCs can be genetically modified with adenoviral vector to secrete high levels of biologically active ECSOD. Our findings suggest that mesenchymal stem cell-based antioxidant gene therapy has the potential to be rapidly implemented as a medical countermeasure against radiation in response to radiological and nuclear emergencies, space radiation exposure, and cancer radiotherapy toxicity.