The mitochondrial antioxidant protein manganese superoxide dismutase (MnSOD) may represent a newtype of tumor suppressor protein. Overexpression of the cDNA of this gene by plasmid or recombinant lentiviraltransfection in various types of cancer leads to growth suppression both in vitro and in vivo. We previouslydetermined that changes in MnSOD expression had bidirectional effects on adriamycin (ADR) when combinedwith nitric oxide (NO). Radiation induces free radicals in a manner similar to ADR, so we speculated thatMnSOD combined with NO would also have a bidirectional effect on cellular radiosensitivity. To examine thishypothesis, TE-1 human esophageal squamous carcinoma cells were stably transfected using lipofectamine witha pLenti6–DEST plasmid containing human MnSOD cDNA at moderate to high overexpression levels or withno MnSOD insert. Blastidicin-resistant colonies were isolated, grown, and maintained in culture. We found thatmoderate overexpression of MnSOD decreased growth rates, plating efficiency, and increased apoptosis. However,high overexpression increased growth rates, plating efficiency, and decreased apoptosis. When combined withNO, moderate overexpression of MnSOD increased the radiosensitivity of esophageal cancer cells, whereas highMnSOD overexpression had the opposite effect. This finding suggests a potential new method to kill certainradioresistant tumors and to provide radioresistance to normal cells.