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However, their expression patterns and functions in melanoma are unclear. The present study aimed to identify the chemokine receptors that play critical roles in melanoma progression and unravel the underlying molecular mechanisms. We found that CCR5 was more abundant in melanoma cells than normal cells and was positively associated with tumor malignancy in clinical patients. Animal experiments suggested that CCR5 deficiency in B16\/F10 or A375 cells suppressed primary tumor growth and lung metastasis, whereas CCR5 overexpression in B16\/F0 cells enhanced primary tumor growth and lung metastasis. CCR5 played a critical role in proliferation and migration of melanoma cells <jats:italic>in vitro<\/jats:italic>. Importantly, CCR5 was required for maintenance of the mesenchymal phenotype of metastatic melanoma cells. Mechanistically, CCR5 positively regulated expression of TGF\u03b21, which in turn induced epithelial\u2013mesenchymal transition and migration via PI3K\/AKT\/GSK3\u03b2 signaling. Collectively, our results establish a critical role of CCR5 expressed by melanoma cells in cancer progression and reveal the novel mechanisms controlling this process, which suggests the prognostic value of CCR5 in melanoma patients and provides novel insights into CCR5\u2010targeted strategies for melanoma treatment. Copyright \u00a9 2018 Pathological Society of Great Britain and Ireland. 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