Transcription factors c-Jun and Fra-1 have been reported to play a role during the initiation and progression in oral squamous cell carcinoma (OSCC). However, cohort studies are rarely reported. Here is an integrative analysis of their prognostic value in OSCC through a multicenter cohort study.313 OSCC patients were included in this study and received regular follow-up. The survival rate and hazard ratios(HR) were generated by survival analysis. The concordance probability and receiver operating characteristic curve area were chosen to measure the model discrimination. High expressions of c-Jun or Fra-1 were associated with poor prognosis, meanwhile the high expression of Fra-1 meant worse prognosis of patients than the high expression of c-Jun. Besides, the interaction effect of c-Jun and Fra-1 was antagonism, when the expression of c-Jun and Fra-1 was both high, the HR was lower than the hazard ratio when only the Fra-1 was at high expression. c-Jun and Fra-1 were both proved to be high risky predictors of death in OSCC, the antagonistic effect suggested that these biomarkers’ activities could be influenced by each other. It may provide a new sight for the studies of OSCC prognosis and treatment.