The functions of telomeric repeat-binding factor 1 (TRF1) and 2 (TRF2) in oral carcinogenesis are largely unexplored. This study examined the relationship between the expression of TRF1 and TRF2 and clinicopathological variables and survival in oral cavity squamous cell carcinoma (OCSCC). Western blotting and immunohistochemistry were used to evaluate the protein expression of TRF1 and TRF2 in paired OCSCC patient specimens. Expression of TRF1 and TRF2 was assessed by immunohistochemistry in 256 OCSCC patients who underwent tumor resection without previous radiotherapy. The results were analyzed using Fisher's exact test. Protein expression of TRF1 and TRF2 was significantly lower in the OCSCC than in the adjacent non-tumor tissue. Reduced TRF1 and TRF2 levels in 256 patients, as revealed by immunohistochemistry, were significantly associated with aggressive clinicopathological features, such as advanced tumor stage (p<0.001) and advanced tumor node metastasis stage (p<0.001). According to Kaplan-Meier analysis, reduced TRF1 expression was significantly correlated with an unfavorable cumulative 5-year overall survival rate (p<0.001). In conclusion, decreased expression of TRF1 was significantly associated with tumor progression and poor prognosis in OCSCC patients.