Approximately 25% of head and neck squamous cell carcinoma (HNSCC) worldwide are associated with high-risk human papillomaviruses (HPV). HPV-positive HNSCCs have a more favorable outcome and greater response to therapy. While chronic HPV infection allows for the evolution of immune evasion mechanisms, viral antigens can still elicit an immune response. Moreover, a robust lymphocytic response is associated with better prognosis in a variety of tumor types including head and neck cancer. This article outlines several mechanisms whereby the observed improved response of HPV-positive tumors to radiotherapy may be related to enhancement of the immune response following radiotherapy.