BACKGROUND: Necroptosis, an alternative mode of programmed cell death (PCD) that overcomes apoptosis resistance, has been implicated in the progression and drug resistance of cancer. The aim of this study is to find the biological and prognostic significance of necroptosis in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Integrated clinical datasets from The Cancer Genome Atlas (TCGA) HNSCC cohort underwent analysis. R package "DESeq2" was used to conduct differential gene expression analysis between normal and tumor tissues in the cohort, resulting in the identification of 2,172 differentially expressed genes (DEGs). A total of 159 necroptosis-related genes (NRGs) were extracted and performed a Venn analysis to identify the optimal necroptosis-related DEGs, resulting in the selection of 25 genes specifically associated with necroptosis in HNSCC. Then prognostic analyze, Cox regression analysis and prognostic model were demonstrated the ability to predict the extent of immunological infiltration in HNSCC. RESULTS: Among these DEGs, five genes ( CONCLUSIONS: We performed a systematic bioinformatic analysis to identify necroptosis-related prognostic genes in HNSCC patients. These genes' prognostic value was synthesized into a predictive nomogram for forecasting HNSCC progression.