In summary, we revealed that matrisome gene expression are associated with HNSCC survival, and established a novel risk score prognostic model based on a signature of six differentially expressed matrisome-related genes (FN1, LAMB4, LAMB3, DMP1, CHAD, and MMRN1), which may also act as potential therapeutic targets for HNSCC. This evidence concerns the gene LAMB4 and head and neck squamous cell carcinoma.