Background and Purpose Adjuvant chemotherapy with 5-fluorouracil (5-FU) prodrugs is now the standard of care for stage I–III oral squamous cell carcinoma (OSCC); however, it remains to be clarified for which patient neoadjuvant chemotherapy with 5-FU prodrugs may be an option. Experimental Approach In the Ryukyu cohort [neoadjuvant chemotherapy with 5-FU prodrugs (UFT or S-1) + bleomycin, neoadjuvant chemotherapy with UFT + bleomycin + cisplatin, and up-front surgery] and Gunma cohort [neoadjuvant chemotherapy with S-1 and up-front surgery], the incidence of distant metastasis was significantly higher in male patients or those with less well differentiated tumors. Key Results Based on these data, we compared the overall survival of male patients who received neoadjuvant chemotherapy and those who received up-front surgery in each cohort. Neoadjuvant chemotherapy with S-1 or S-1 + bleomycin significantly increased overall survival rates in male patients. The ratio of male patients correlated with less well differentiated tumors. Conclusion and Implications Data in The Cancer Genome Atlas revealed that the expression of DNA repair genes correlated with male sex and less well differentiated tumors, while higher Myd88 expression and type I interferon activity were associated with female sex and well-differentiated tumors.