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Human papillomavirus-associated squamous cell cancer of the head and neck (HPV-HNSCC) represents an important subgroup of head and neck cancer that is characterized by distinct epidemiologic, clinical, and pathologic features including a relatively constant microscopic appearance. For those cancers that deviate from the morphologic prototype, an association with HPV may not be recognized and accurate tumor classification may not be achieved. We have identified 22 cases of HPV-HNSCC with well-developed lymphoepithelial features including tumor cells with syncytial cytoplasm, vesicular nuclei, and large central nucleoli dispersed in an inflammatory background as cell clusters or single cells. The pattern closely resembles Epstein-Barr virus (EBV)-induced undifferentiated carcinoma of the nasopharynx. Indeed, 3 of the carcinomas presenting as lymph node metastases were originally misdiagnosed as metastatic nasopharyngeal carcinoma. Unlike nasopharyngeal carcinoma, the cases were of oropharyngeal origin, p16 positive by immunohistochemistry (22 of 22, 100%), HPV-16 positive by in-situ hybridization (19 of 22, 86%), and EBV negative by in-situ hybridization (21 of 21, 100%). Like conventional HPV-related HNSCC, the cases tended to occur in patients below 60 years of age (77%), men (73%), and nonsmokers (59%). For carcinomas of the head and neck that exhibit lymphoepithelial features, one cannot assume an EBV-driven process by morphology alone. HPV testing has disclosed a previously unrecognized morphologic variant of HPV-HNSCC that is microscopically indistinguishable from EBV-related carcinoma. For lymphoepithelial carcinomas presenting as cervical lymph node metastases, testing for HPV and EBV is mandatory.