The results of gender-disaggregated survival analyses showed that high E2F4 expression could lead to poor prognosis in both male and female HNSCC patients, high expressions of E2F5, E2F6, and E2F7 were associated with poor OS of female HNSCC patients, while high E2F2 and E2F8 expressions were positively correlated with the OS of male HNSCC patients. The gene discussed is E2F6; the disease is head and neck squamous cell carcinoma.