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5-azacytidine is a cytidine analogue with cytotoxic and cytostatic activity, currently utilized for the treatment of myelodysplastic syndromes. The cytostatic activities of low-dose 5-azacytidine are attributed to its incorporation into the DNA and RNA of mammalian cells, which influences epigenetic regulation, cell cycle progression, and protein expression. We observed that treatment with 5-azacytidine significantly radio-sensitizes androgen-independent prostate cancer cells, synergistically enhancing the overall efficiency of radiation treatment both in vivo and in vitro. Furthermore, we found that exposure of androgen-independent prostate cancer cells to 5-azacytidine impairs or delays the repair of radiation induced DNA double-strand breaks through the non-homologous end-joining pathway. This observation explains the radio-sensitizing potential of 5-azacytidine and constitutes the first conclusive evidence for a DNA repair defect introduced by this compound. In addition, we found that this DNA repair defect was not introduced by the 2’-deoxy derivative of 5-azacytidine. From this finding we infer that the inhibitory effects of 5-azacytidine on DNA repair are primarily mediated by its incorporation into the RNA. We suggest that a combined treatment with 5-azacytidine and ionizing radiation would be a good candidate for clinical trials, not necessarily limited to prostate cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 189.