Using significant factors identified in the univariate analysis, multivariate analysis confirmed that high FOXD1 expression (HR = 1.849, 95% CI: 1.280-2.670, P = 0.001), positive perineural invasion (HR = 2.051, 95% CI: 1.436-2.931, P = 7.90E-05), and advanced pathologic stage (HR = 1.739, 95% CI: 1.051-2.877, P = 0.31) were independent risk factors for poor OS in patients with HNSCC. The gene discussed is FOXD1; the disease is head and neck squamous cell carcinoma.