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. Here, LAMB3 is linked to head and neck squamous cell carcinoma.