Epigenetic therapy by DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza 2'dC) is clinically effective in acute myeloid leukemia; however, it has shown limited results in treatment of breast cancer and has significant toxicity to normal cells. Green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has anti-cancer and DNA demethylating properties with no significant toxicity toward normal cells. Therefore, the objective of this study was to evaluate the therapeutic efficacy of a combination of non-toxic, low dose of 5-aza 2' dC with EGCG, on growth inhibition of breast cancer cells. Human breast cancer cell lines (MCF-7, MDA-MB 231) and non-tumorigenic MCF-10A breast epithelial cells were treated with either 5-aza 2' dC, EGCG, or their combination for 7 days. Cell growth inhibition was determined by cell count, cell viability, cell cycle, and soft agar assay, whereas genes expression changes were determined by quantitative real-time PCR and/or Western blot analysis. Histone modifications and global DNA methylation changes were determined by Western blot and RAPD-PCR, respectively. The results revealed significantly greater inhibition of growth of breast cancer cells by co-treatment with 5-aza 2' dC and EGCG compared to individual treatments, whereas it has no significant toxicity to MCF-10A cells. This was further confirmed by gene expression analysis. Changes in DNA methylation and histone modifications were also greater in cells with combination treatment. Findings of this study suggest that potentiation of growth inhibition of breast cancer cells by 5-aza 2' dC and EGCG combination treatment, at least in part, is mediated by epigenetic mechanism.