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Head and neck squamous cell carcinomas (HNSCC), emerging in the mucosa of the upper aerodigestive tract, are associated with either the classical risk factors, tobacco and alcohol consumption, or with infections with high-risk types of the human papillomavirus (HPV). Depending on the involvement of HPV, HNSCC follow different pathways of carcinogenesis and show distinct clinical presentations regarding survival, prognosis and treatment response. For instance, HPV-driven HNSCC exhibit an enhanced radiation response compared to their typically radioresistant HPV-negative counterparts. Although radiosensitivity of HNSCC has been studied by many research groups, the major causes for the difference in radiation responses between HPV-driven and HPV-negative HNSCC are still an open question. In this mini review, we discuss the reported cellular and immunological factors involved in the enhanced radiation response in HPV-driven HNSCC, focusing on the vital role of the immune response in the outcome of HNSCC radiotherapy.