In the present study, we demonstrated that the CCL2-CCR4 axis, not CCL2-CCR2 signaling, mediates the CCL2-induced migration and invasion of human HNSCC cells and targeted inhibition of CCR4 significantly inhibit the invasion and metastasis of HNSCC xenografts in the nude mouse without causing relapse during the cessation of CCL2 antibody therapy. This evidence concerns the gene CCR4 and head and neck squamous cell carcinoma.