Mycosis fungoides (MF) and Sézary syndrome (SS) are two most common types of cutaneous T-cell lymphoma (CTCL). Despite advances in understanding the pathogenesis of MF and SS, effective treatments remain limited. CC chemokine receptor 4 (CCR4) is highly expressed on CTCL cells and serves as a great therapeutic target. Mogamulizumab, an FDA-approved anti-CCR4 antibody, has shown efficacy in treating MF/SS; however, its side effects have raised concerns, underscoring the need for more effective and less toxic CCR4-targeted therapies. While small molecule CCR4 antagonists have been studied in other diseases involving CCR4+ Th2 cells and regulatory T-cells, but their effects in CTCL have not been previously explored. This study assessed the effects of two small molecule CCR4 antagonists, C021 (Class I) and AZD2098 (Class II), in MF derived cell line (MJ) and SS derived cell line (HuT 78) in vitro and in vivo. As results, both C021 and AZD2098 inhibited chemotactic responses to CCL17 and CCL22 in MJ and HuT 78 cells. However, only C021 downregulated CCR4 expression, inhibited cell proliferation, induced cell apoptosis and cell cycle arrest, and decreased colony formation in MJ and HuT 78 cells in vitro. Furthermore, only C021 inhibited tumor growth in CTCL xenograft mice in vivo. These findings suggest that Class I CCR4 antagonists such as C021 exerts more potent anti-tumor effects on CTCL cells in vitro and in vivo compared to Class II CCR4 antagonists like AZD2098, highlighting its potential for clinical application.