Background:The study aims to analyze Thymidylate Synthase (TS) and Dihydropyrimidine Dehydrogenase (DPD) Expressions on 5-Fluorouracil in Oral Squamous Cell Carcinoma (OSCC). Methods:50 oral squamous cell carcinoma samples were taken from non-treated cancer patients at Hiroshima University Dental Hospital. The patients were investigated for TS, that included 36 males and 14 females. Additionally, 31 patients were evaluated for DPD that included 22 males and 9 females.Results:The samples had also undergone clinical and pathological evaluation, immunohistochemical staining, evaluation of immune-staining, enzymatic expression, and statistical analyses. Mean age of the population was 62.1 years. Conclusion: Over-expression of TS contributes significantly to the resistance of 5-FU treatment; while inhibition of intra-tumoral DPD increases the sensitivity level. TS levels are not only predictive of 5-FU response, but also prognostic in clinical value of non-treated cancer patients.