Resistance to chemotherapy is a major hurdle in the treatment of cutaneous T cell lymphoma. Histone deacetylase (HDAC) inhibitors are known to display antitumor activity in different tumor types, including melanoma, and to reverse epigenetic repression of tumor suppressor genes. Some HDAC inhibitor has begun to be used for cutaneous T cell lymphoma patients in Japan. In this study, we tested the antitumor effect of the HDAC inhibitor MS-275 in combination with retinoic acid Am80 on two human cutaneous T cell lymphoma cell lines in vitro and in vivo. Treatment of MS-275 showed a dose-dependent inhibitory effect on SeAx and MJ cell lines in a XTT assay. These cell lines were relatively resistant to Am80. A greater inhibitory effect (up to 80%) was achieved with a combination of MS-275 and Am80 compared with each agent alone. The lack of RARβ2 gene expression was associated with histone deacetylation and gene methylation at the promoter level. Treatment with the combination of MS-275 and Am80 restored retinoid sensitivity by reversing RARβ2 epigenetic silencing, which was verified by ChIP assay using histone H4. P21 was induced in both cell lines but the biological effect of MS-275 was G1cell cycle arrest in MJ and apoptosis in the SeAx cell line. Both of active and repressive histone markers of at promoter site of RARβ2 were upregulated by the treatment with the combination of MS-275 and Am80. Tumor volume analysis in NOD scid mice showed that the treatment of the combination of MS-275 and Am80 had a significant inhibitory effect on tumor growth in vivo. These results suggest that the HDAC inhibitor MS-275 restores the sensitivity of retinoic acid and has a greater antitumor activity in combination with Am80 in cutaneous T cell lymphomas by reverting epigenetic silencing of RARβ2. The combination of HDAC inhibitors and retinoids represents a novel therapeutic approach for cutaneous T cell lymphoma that warrants clinical testing.