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There is abundant epidemiologic and virologic evidence that high-risk human papillomaviruses (HPVs) are tumorigenic in human epithelia, particularly in the cervix, where HPV infection is necessary for cancer development. HPV DNA has been detected in a proportion of head and neck squamous cell carcinomas (HNSCCs) in numerous case series. The mere presence of the virus in tumor specimens, by itself, does not imply a causal relationship. However, recent studies support an etiologic role for HPVs in a subset of HNSCC, particularly poorly differentiated tumors arising from Waldeyer’s tonsillar ring. Epidemiologic studies have shown that exposure to HPV increases the risk of HNSCC, and HPV infection may interact with alcohol and tobacco exposure in tumor promotion. Molecular studies indicate that transcriptionally active virus is confined to tumor cells. It will be important to clarify further the role that HPV has in HNSCC development, because HPV-based therapeutic vaccines which are currently being developed for cervical cancer may also be of benefit in the management of HNSCC.