As an important process in cancer immunotherapy, T cell-mediated tumor killing (TTK) enhances the immune response of patients. However, the role of TTK in Head and Neck Squamous Cell Carcinoma (HNSCC) patients still needs further exploration. Therefore, we comprehensively analyzed the gene expression information and clinical characteristics of 1063 HNSCC in five cohorts. Univariate regression, differential expression analysis, and gene mutation profiling were combined to identify the important genes regulating the sensitivity of tumor cells to T cell-mediated killing (GSTTK) in HNSCC. A total of 20 GSTTK were identified as important genes of HNSCC. Patients were divided into C1 and C2 subgroups (TTK patterns) and displayed significant prognostic differences. Patients with C2 subtype had dismal prognosis characteristic compared to C1 subtype in all validation cohorts. Patients with C1 subgroup exhibited robust immune profile and C1 subgroup patients were significantly enriched in metabolically relevant functions. Notably, the multi-omics analysis found that C1 subgroup have higher mutation burden and C2 subgroup patients had significantly higher copy number variation. Drug sensitivity analysis found that multiple first-line chemotherapeutic drugs were more sensitive in patients with subgroup C1. In conclusion, the establishment of GSTTK provides guidance and assistance to clinicians in the personalized management and treatment of HNSCC patients.