We retrospectively studied young patients with head and neck squamous cell carcinoma (HNSCC) to identify factors associated with disease-specific survival (DSS). Patient and tumor characteristics of patients aged ≤45 who received treatments for non-metastatic HNSCC were collected to identify factors associated with DSS. Proportional hazards regression was applied separately for surgical and non-surgical patients. 230 patients were included. Surgical and non-surgical patients had similar DSS. Higher pathologic stages, positive margins, perineural invasion (PNI), extranodal extension and negative HPV status were associated with worse DSS for surgical patients and negative HPV status for non-surgical patients. In the multivariate analysis, pathologic stages, positive margins, and PNI were associated with worse DSS in surgical patients. Pathologic stages, positive margins, and PNI are independently associated with worse DSS in young surgical HNSCC patients. PNI is a uniquely strong prognostic factor for young patients.