The genotype of the fibroblast growth factor receptor 4 (FGFR4) gene and TP53 mutation have been reported as prognostic factors for cancers of the head and neck, bladder, breast and colon. To determine whether they are applicable for oral squamous cell carcinoma (OSCC), we investigated these two genes in OSCC samples from 150 patients who had undergone radical surgery and in 100 cancer-free individuals. In OSCC, the FGFR4 Gly388Arg polymorphism and the presence or absence of mutation in TP53 did not show a significant association with the clinicopathological features of the tumors at surgery. However, the FGFR4 Arg388 allele, as well as mutations in TP53, was found to be closely associated with poor prognosis. Moreover, these two parameters synergistically affected the survival of OSCC patients. During 60 months of observation after radical surgery, a majority of patients with homozygous Arg388 FGFR4 plus mutated TP53 died of cancer, whereas >90% patients carrying homozygous Gly388 FGFR4 plus wild-type TP53 survived. Therefore, the FGFR4 Gly388Arg polymorphism and TP53 mutations, as well as their combinations, are excellent predictors of the prognosis for OSCC patients.