BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous malignancy with poor prognosis. Dysregulation of E2F transcription factors (E2Fs), which control cell proliferation and apoptosis, is implicated in HNSCC pathogenesis. This study explores HNSCC molecular heterogeneity via E2Fs expression, identifies distinct subtypes, and develops a prognostic model that integrates gene expression, immune infiltration, and drug sensitivity. METHODS: We analyzed the TCGA-HNSC dataset (n = 494) and classified samples based on the expression of eight E2Fs using ConsensusClusterPlus. The optimal number of clusters (k = 2) was determined with the getOptK() function, which assesses cluster stability via internal consistency metrics. Differentially expressed genes between subtypes were identified with limma, and functional annotation was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. A prognostic model was constructed using LASSO regression on genes significant in univariate Cox analysis and validated in an independent GSE41613 dataset (n = 97). Immune cell infiltration was estimated using CIBERSORT, and drug sensitivity predicted via pRRophetic. Confounding factors such as HPV and smoking status were not included due to incomplete data. RESULTS: Two distinct E2F-based subtypes emerged. Cluster 1, characterized by lower E2Fs expression, exhibited poorer overall survival (log-rank, p = 0.035) and was enriched in genes related to epidermal development, keratinocyte differentiation, and IL-17 signaling. In contrast, Cluster 2 showed higher E2Fs expression, better survival, and enrichment in genes associated with DNA replication and repair. Notably, high-risk patients demonstrated increased infiltration of M0 and M2 macrophages (p < 0.05), suggesting an immunosuppressive tumor microenvironment that adversely affects prognosis. Our seven-gene prognostic model (AREG, CXCL14, FAM83E, FDCSP, ARHGAP4, EPHX3, and SPINK6) exhibited robust performance with AUCs of 0.692, 0.673, and 0.679 for 1-, 3-, and 5-year survival, a C-index of 0.66, and good calibration. High-risk patients also showed greater sensitivity to targeted agents such as pazopanib and imatinib. CONCLUSIONS: These findings reveal two distinct E2F-based molecular subtypes of HNSCC that differ in prognosis, functional pathways, immune infiltration, and drug sensitivity. The prognostic model offers valuable risk stratification and identifies potential biomarkers and therapeutic targets, warranting further experimental and clinical validation.