Tumor-associated macrophages (TAMs) promote cancer cell proliferation, invasion, and metastasis by producing various mediators. Although preclinical studies demonstrated that TAMs preferentially express CD163 and CD204, the TAM subsets in oral squamous cell carcinoma (OSCC) remain unknown. In this study, we examined the expression and role of TAM subsets in OSCC. Forty-six patients with OSCC were analyzed for expression of TAMs in biopsy samples by immunohistochemistry. We examined TAM subsets and their production of immune suppressive molecules (IL-10 and PD-L1) in peripheral blood mononuclear cells from three OSCC patients by flow cytometry. CD163 was detected around the tumor or connective tissue, while CD204 was detected in/around the tumors. Flow cytometric analysis revealed that CD163⁺CD204⁺ TAMs strongly produced IL-10 and PD-L1 in comparison with CD163⁺CD204⁻ and CD163⁻CD204⁺ TAMs. Furthermore, the number of activated CD3⁺ T cells after co-culture with CD163⁺CD204⁺ TAMs was significantly lower than that after co-culture with other TAM subsets. In clinical findings, the number of CD163⁺CD204⁺ TAMs was negatively correlated with that of CD25⁺ cells and 5-year progression-free survival. These results suggest that CD163⁺CD204⁺ TAMs possibly play a key role in the invasion and metastasis of OSCC by T-cell regulation via IL-10 and PD-L1 production.