Tumor budding (TB) is a well-established prognostic biomarker in HPV-negative head and neck squamous cell carcinoma (HNSCC) and an emerging prognostic biomarker in HPV-positive HNSCC. The molecular determinants and mechanisms underlying TB are incompletely understood. Here, we profile an in-house cohort of HPV-negative HNSCCs by MS-based proteomics to uncovered molecular correlates of TB in HNSCC.