OBJECTIVES: The myeloid-derived suppressor cells (MDSCs) frequently have a high expansion in cancer patients. This research explored whether administration of β-glucan could increase anti-tumor immunity in oral squamous cell carcinoma (OSCC) patients. MATERIALS AND METHODS: This study evaluated the MDSC level of circulating blood as CD33(+) /CD11b(+) /HLA-DR(-/low) by flow cytometry in 30 healthy donors (HDs, group I), in 48 oral squamous cell carcinoma (OSCC) patients before and after 14-day pre-operative administration of β-glucan (group II), and in 52 OSCC patients without taking β-glucan (group III). RESULTS: A significantly higher mean MDSC level was observed in 100 OSCC patients than in 30 HDs (p < 0.001). There was a significant reduction of the mean MDSC level in group II patients after taking β-glucan (p < 0.001). Moreover, we discovered a significantly higher recurrence-free survival (RFS) in group II than in group III patients (p = 0.026). Finally, the multivariate Cox regression further identified the MDSC level ≤ 1% and administration of β-glucan as more favorable prognostic factors for OSCC patients. CONCLUSION: Preoperative administration of β-glucan can augment anti-tumor immunity and increase RFS rate via subversion of suppressive function of MDSC in OSCC patients.