Purpose Cutaneous T cell lymphomas (CTCL) are a heterogeneous group of malignancies that despite available therapies commonly relapse. The emergences of combination epigenetic therapies in other hematologic malignancies have made investigation of such combinations in CTCL a priority. Here, we explore the synergistic anti-proliferative effects of romidepsin, an HDAC inhibitor, and azacitidine, a demethylating agent, combination in CTCL. Experimental Design The growth inhibition under combination treatment and single agent was explored by the MTT cell viability assay and the Annexin V/ Propidium Iodide apoptosis assay in different CTCL cell lines and tumor cells derived from Sézary syndrome patients. Quantitative analysis of dose-effect relationship of romidepsin and azacitidine was done by the CompuSyn software. Investigation of mechanism of action was performed by flow cytometry, immunoblotting, qRT-PCR arrays and chromatin immunoprecipitation. Global CpG methylation-sequencing was utilized to study genome methylation alteration under the treatment modalities. Results The combination of romidepsin and azacitidine exerts synergistic anti-proliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL. We identified genes that were selectively induced by the combination treatment, such the tumor suppressor gene RhoB that is linked to enhanced histone acetylation at its promoter region in parallel with pronounced expression of p21. Global CpG methylation-sequencing in a CTCL cell line and tumor cells demonstrated a subset of genes with a unique change in methylation profile in the combination treatment. Conclusions The synergistic anti-proliferative effects of romidepsin and azacitidine combination treatment justify further exploration in clinical trials for advanced CTCL.