Abstract Background Oral squamous cell carcinoma (OSCC) is the most common malignancy in oral maxillofacial region. Although modest improvements in the survival rates have been reported, the prognosis remains unsatisfactory. Tumor infiltrating immune cells have been proved playing critical roles in tumor prognosis. We conducted this study to evaluate the predictive value of CD4+ T cells, T-bet+ Th 1 cells, CD8+ T cells, CD57+ NK cells and CD68+ macrophages for OSCC outcome. Methods 78 OSCC patients were included and followed up for at least 3 years. Clinical data and Paraffin-embedded samples were collected. CD4, CD8, T-bet, CD57 and CD68 expressions were examined by immunohistochemistry. The Kaplan –Meier method, log-rank test and Cox proportional hazards model were used to estimate the prognostic factors for Overall survival. ROC and AUC were used to evaluate the prognostic value. RESULTS Multivariate analysis revealed that no lymph node involvement, lower CD4 (+) T cells and high CD57 (+) NK cells infiltration were all significantly related with longer survival (P < 0.01). The respective predictive accuracy of CD4+ T cells, CD8+ T cells and CD57+ NK cells were all superior to TNM staging. CD57 expression provided the highest accuracy (AUC=0.759; 95% CI, 0.652–0.886). Conclusion Our study highlighted the predominant role of innate immune system in tumor immunity. Adaptive immunity seemed to be the major victim of immune tolerance. When compared to TNM staging, CD4, CD8 and CD57 expression significantly improves mortality prediction for OSCC patients. This study will provide new strategies to patient management of OSCC.