Nasopharyngeal carcinoma (NPC) is very common in Southern China and Southeast Asian countries. To explore a novel and more effective approach to NPC therapy, a combined strategy of suicide genes and radiation was designed in this study. Five suicide gene expression cassettes, yeast CD, yeast CD/UPRT, and yeast CDglyTK gene controlled by CMV, and Egr-1 and a synthetic CMV-enhanced Egr-1 promoter (CE) were constructed in an expression vector p11MS. The expression of suicide genes in NPC CNE-2 cells were detected by RT-PCR and Western blot. The cytotoxicity of suicide gene therapy and radiation were analyzed by MTT assay. An animal study in which yeast CD/UPRT-expressing CNE-2 tumors in nude mice were treated with 5-FC and radiation was also developed. Our results revealed that p11MSCEyCD/UPRT and p11MSCEyCDglyTK are superior over three other constructs in the killing of NPC cells in vitro. We combined suicide gene-expressing tumors, 5-FC treatment, and radiation in vivo and found that the tumors greatly regressed, some disappeared completely in 3 nude mice in the yCD/UPRT group, and a significant difference of tumor volumes was observed between this group and the other four groups (p < 0.05). Our results indicated that suicide gene therapy and radiation have a synergic effect on NPC therapy, and the combined strategy of radiogene therapy is of great potential as a substitute for the traditional method, radiation alone, in NPC therapies.