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As both tumor hypoxia and an immunosuppressing tumor microenvironment hamper the anti-tumor activity of radiotherapy in head-and-neck squamous cell carcinoma (HNSCC), we aimed to develop an immunohistochemistry-based hypoxia-immune classifier. 39 patients receiving definitive chemoradiation for HNSCC within a prospective trial were included in this analysis. Baseline tumor samples were analyzed for the hypoxia marker carbonic anhydrase IX (CAIX) and tumor-infiltrating lymphocytes (TILs) and were correlated with [18F]-misonidazole ([18F