In summary, our study suggested that CXCL1, CXCL2, CXCL3, CXCL8, and CXCL12 have potential value as new prognosis markers and therapeutic targets for patients with HNSCC, while CXCL9, CXCL10, CXCL13, CXCL14, and CXCL17 could be used as functional prognosis biomarkers to identify better survival rate subgroups of patients with HNSCC. Here, CXCL13 is linked to head and neck squamous cell carcinoma.