EIF2S1, CAV1, RAN, ANXA5, CYCS, CFL1, MYC, HSP90AA1, PKM, and HSPA5 overexpression was substantially related to a poor prognosis in patients with HNSCC, and 96 hub genes showed a striking centrality within the PPI network. Here, EIF2S1 is linked to head and neck squamous cell carcinoma.