Myeloid‐derived suppressor cells (MDSC) represent a heterogeneous population and have the potential to suppress immune responses via diverse mechanisms. In recent studies, a new subset of MDSC was identified by the markers CD14⁺ and HLA‐DR⁻ in the peripheral blood from cancer patients. In this study, we investigated the proportions and characteristics of CD14⁺ HLA‐DR⁻ cells in patients with squamous cell carcinoma of the head and neck (SCCHN). As expected, the percentage of CD14⁺ HLA‐DR⁻ cells was significantly elevated in patients relative to healthy donors and the sorted CD14⁺ HLA‐DR⁻ cells were able to suppress effectively both the proliferation and IFN‐γ production of anti‐CD3/anti‐CD28 stimulated T cells, suggesting that CD14⁺ HLA‐DR⁻ cells in patients with SCCHN contribute to the immune suppressive status. Furthermore, CD14⁺ HLA‐DR⁻ cells revealed a higher level of CD86 and PD‐L1 expression and transforming growth factor (TGF)‐β production than CD14⁺ HLA‐DR⁺ cells. Addition of anti‐CD86 mAb, anti‐PD‐L1 mAb and anti‐TGF‐β mAb partially restored T‐cell proliferation and IFN‐γ production, respectively, indicating that the suppressive effects of CD14⁺ HLA‐DR⁻ cells appear to be mediated by various molecules, including coinhibitory molecules and cytokines. Our data suggest that CD14⁺ HLA‐DR⁻ cells act as potent immunosuppressive cells and particularly contribute to tumor escape from the host immune system in patients with SCCHN. (Cancer Sci 2012; 103: 976–983)