Background: Colorectal carcinoma (CRC) is a leading cause of cancer related deaths. Despite recent efforts to develop novel biologic therapies, most patients die of metastatic disease. Epigenetic alterations including DNA hypermethylation and histone modifications are frequent and early events in CRC. These epigenetic alterations which lead to transcriptional silencing have been found to be reversible in cultured systems eventually leading to re-expression of silenced genes. Recently FDA has approved demethylating agents for therapy and they are now successfully used in myelodysplastic syndromes. However demethylating drugs have not shown benefit in solid tumors due to issues such as bioavailability of the drug and cytotoxicity at high doses. We have previously shown that combination epigenetic therapy using demethylating drugs and histone deacetylase inhibitors (HDACi) shows synergism in reactivating genes. In the current study we explore the utility of combination epigenetic therapy in CRC cell lines using different concentrations of 5’-Azacytidine (AZA, a demethylating agent) and SNDX-275 (HDACi).Methods: Combination epigenetic therapy with different doses of AZA and SNDX-275 were tested in HCT116 and RKO. Drug treatment regimens include a) AZA alone, 4 concentrations (50nM, 500nM, 1µM and 5µM) b) SNDX-275 alone (1 µM) c) Combination of AZA and SNDX-275. DNA and RNA were extracted and analyzed for methylation and expression status of genes including TFPI2 and SFRP1. Results: TFPI2 and SFRP1 which are methylated and silenced in HCT116 and RKO were re-expressed and partially demethylated after the treatments with high dose AZA alone (500 nM and higher) or in combination with SNDX-275. Additionally, TFPI2 was re-expressed and partially demethylated by low dose AZA (50nM) alone or in combination with SNDX-275. Interestingly, SFRP1 although not re-expressed by low dose AZA alone (50nM), was re-expressed and partially demethylated when low dose AZA was combined with SNDX-275 implying synergy. Conclusions: Low dose AZA (50nM) either alone or in combination with SNDX-275 is capable of demethylating and re-expressing genes, with effect comparable to high dose AZA. Our results may have important clinical implications since higher doses cannot be achieved in patients due to instability of AZA. Combination of low dose AZA and SNDX-275 may provide a more mechanistic, epigenetically driven rather approach than cytotoxicity driven approach of high dose AZA. This may provide a new pharmacologic model for investigation in clinical treatment of solid tumors including CRC.