BACKGROUND: Immunotherapy has improved the outcomes for some patients with head and neck squamous-cell carcinoma (HNSCC). However, the low and variable response rates observed highlight the need for robust response biomarkers to select patients for treatment. PATIENTS AND METHODS: We assembled and analyzed a large HNSCC dataset, encompassing 11 clinical cohorts including 1232 patient samples, spanning a variety of disease subtypes and immune checkpoint blockade (ICB) treatment types, tissue sources, data modalities, and timing of measurements. We conducted a comprehensive evaluation of the predictive power of various cell types, traditional biomarkers, and emerging predictors in both blood and tumor tissues of HNSCC patients. RESULTS: Tumor B-cell infiltration emerged as a strong and robust predictor of both patient survival and ICB response. It outperformed all other established biomarkers of response to ICB, including the tertiary lymphoid structure signature and numerous T-cell-based signatures. B-cell infiltration was associated with a 'hot' antitumor microenvironment that promotes tumor eradication. Furthermore, B-cell levels in peripheral blood mononuclear cells (PBMCs) correlated strongly with tumor B-cell levels and demonstrated high predictive value for ICB response, with high odds ratios (≥7.8) in two independent clinical cohorts. CONCLUSION: B-cell abundance, whether assessed in PBMCs or tumor tissues, is one of the strongest predictors of ICB response in HNSCC. For translation to patient care, measuring B-cell abundance in PBMCs via cytometry offers a practical and accessible tool for clinical decision making.