Failure to control nasopharyngeal carcinomas (NPC) is mainly due to a portion of radioresistant phenotype. Identifying gene targets for radiosensitization is an important strategy in improving anticancer treatments. Exposure of cells to ionizing radiation leads to the formation of reactive oxygen species that are associated with radiation-induced cellular apoptosis and necrosis. The antioxidant enzyme manganese superoxide dismutase (SOD2) catalyzes the dismutation of the superoxide anions into hydrogen peroxide. We reasoned that SOD2 could contribute to the radioresistant phenotype in NPC cells. We compared CNE1 cells with CNE2 cells in radiation character and SOD2 protein. SOD2 gene silencing through the plasmid transfer using a microRNA interference optimized for transcription in NPC cell lines inhibited the radioresistance of human NPC cells. We compared radio-resistant NPC with radiosensitive NPC in SOD2 expression. CNE1 cells and CNE2 cells demonstrated dose-modifying factors at 10% isosurvival of 1.529 and 1. CNE1 cells were 1.94-fold higher than CNE2 cells at SOD2 protein baseline, and CNE1 cells exposed to ionizing radiation demonstrated 1.15- to 1.39-fold increase in SOD2 immunoreactive protein. Radioresistance in CNE1 cells was reduced following expression of miRNA targeting SOD2. Radioresistant tumors (11/23) were SOD2-positive, and 2/46 radiosensitive tumors were SOD2-positive before commencement of radiotherapy. The results presented suggest that SOD2 expression can participate in radioresistance of NPC, being markers of a subset of tumors in which routine radiation treatment failure is likely. Combination of the SOD2 gene silencing therapy and conventional radiotherapy should be attempted to improved cancer therapy for NPC.