BACKGROUND: To identify the prognostic markers of oral squamous cell carcinoma (OSCC), the genetic heterogeneity of the pathological stages was investigated. METHODS: The data of 295 patients with primary OSCC obtained from the Cancer Genome Atlas were studied. The genetic prognostic landscape of the pathological stages was systematically analyzed by Cox regressions, Fisher's exact tests, and Gene Ontology (GO) enrichment. RESULTS: Stage 4 patients had a poor prognosis in univariate and multivariate Cox models. Transforming growth factor-beta (TGF-β) pathway alterations were found more frequently in stage 4, whereas alterations in cell cycle pathways were significant in stages 1, 2, and 3. The differentially mutated genes were divided into three groups: risk genes of high stage, hazardless genes, and risk genes of low stage. The risk genes of low stage (RNF112, AKR7L, ZSCAN5C, and ZPBP) were independent prognostic factors with stage 4 and treatment modality in multivariate Cox regressions. Additionally, in genetic interaction analysis, NOMO1 and ZNF333 had a high co-occurrence in high stage, and WIZ had high co-occurrence in low stage. In GO enrichment, the prognostic genes were clustered at the functional term of RNA polymerase II transcription, and ZNF333 had an association with RNA transcription. CONCLUSION: The genetic mutation type and ratio of tumor heterogeneity are different for each stage of OSCC, and stratification of OSCC patients with differential therapeutic efficacy is needed. Risk genes of both high and low stages must be identified in patients diagnosed with low-stage OSCC. Mutations in NOMO1, ZNF333, and WIZ should be considered as potential prognostic markers.