Objective: Human papillomavirus (HPV) associated oropharyngeal carcinoma has been identified as a distinct entity within squamous cell carcinoma of the head and neck and is preponderantly restricted to palatinal tonsils and base of tongue. These two primary locations have for long -and HPV-associated carcinomas have recently -been associated with the clinical situation of cancer of unknown primary (CUP). Method: To investigate the relationship between HPV and CUP in detail, we studied 26 consecutive patients who initially presented as CUP and were finally diagnosed with carcinomas of these two locations. Results: Twenty-one carcinomas (81 %) proved to be positive for high-risk HPV (p16 and polymerase chain reaction). They were frequently very small (smallest: 0.3 cm; 6 cases: ≤ 0.6 cm; on average 0.9 cm) and located in a deep, submucosal position. Conclusion: This demonstrates an overrepresentation of HPV-associated carcinoma in patients who were initially diagnosed with CUP, supporting a strong causal relationship between HPV-association and CUP. The frequent manifestation as CUP presumably is caused by the unusual predisposition for small size and submucosal location, combined with frequent and early lymphatic metastization. In order not to miss these small, clinically occult carcinomas, consequent interdisciplinary cooperation and meticulous histological work-up is mandatory.