Simple Summary For clinicians, rapid diagnosis of early neoplastic lesions and prediction of treatment response are two key aspects to guide their choice of treatment. Current histological markers are based on proliferation, differentiation states or specific cell function, but do not take full advantage of tumor characteristics. We show that the subnuclear distribution of CENP-A, the centromeric histone variant, provides, for both aspects, information distinct from and independent of commonly used markers. Our study reveals that in locally advanced head and neck squamous cell cancer patients, the subnuclear distribution of CENP-A at the time of diagnosis is an independent predictive marker of local disease control and curability by concurrent chemoradiation therapy. We provide evidence for the clinical applicability of this CENP-A labeling as a cost-effective marker regardless of genetic alterations in the tumor, perfectly compatible with the clinical time constraints in the course of therapy. Abstract Effective biomarkers predictive of the response to treatments are key for precision medicine. This study identifies the staining pattern of the centromeric histone 3 variant, CENP-A, as a predictive biomarker of locoregional disease curability by chemoradiation therapy. We compared by imaging the subnuclear distribution of CENP-A in normal and tumoral tissues, and in a retrospective study in biopsies of 62 locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated by chemoradiation therapy. We looked for predictive factors of locoregional disease control and patient’s survival, including CENP-A patterns, Ki67, HPV status and anisokaryosis. In different normal tissues, we reproducibly found a CENP-A subnuclear pattern characterized by CENP-A clusters both localized at the nuclear periphery and regularly spaced. In corresponding tumors, both features are lost. In locally advanced HNSCC, a specific CENP-A pattern identified in pretreatment biopsies predicts definitive locoregional disease control after chemoradiation treatment in 96% (24/25) of patients (OR = 17.6 CI 95% [2.6; 362.8], p = 0.002), independently of anisokaryosis, Ki67 labeling or HPV status. The characteristics of the subnuclear pattern of CENP-A in cell nuclei revealed by immunohistochemistry could provide an easy to use a reliable marker of disease curability by chemoradiation therapy in locally advanced HNSCC patients.