BACKGROUND: Podoplanin is a mucin-like glycoprotein that is important in lymphangiogenesis but not blood vessel formation. Recent studies suggested a potential role of podoplanin in certain tumor cells. The purpose of the current study was to determine the role of podoplanin in head and neck squamous cell carcinoma (HNSCC). METHODS: Podoplanin expression was analyzed in 35 patients with HNSCC including 16 oral tumors and 19 hypopharyngeal tumors by immunohistochemical analysis and the association between the podoplanin expression status and patients' clinical and pathologic characteristics was evaluated. An independent set of 60 patients with oral tongue cancer was then analyzed for associations between the podoplanin expression status and patients' clinical and pathologic characteristics, including survivals. RESULTS: Podoplanin was not expressed in normal oral epithelial cells but was detected in some hyperplastic and dysplastic lesions. High podoplanin expression was found in 20 (57%) of the 35 tumors and was more frequent in tumors with lymph node metastasis, particularly for tumors in the oral cavity. In the second set of 60 oral tongue cancers, 36 (60%) expressed high levels of podoplanin. Patients whose tumors expressed high levels of podoplanin had a statistically significantly higher rate of lymph node metastasis (P < .0001). Patients with lymph node metastasis and high-level podoplanin showed the shortest disease-specific survival (P = .0004) than other patients. CONCLUSIONS: Podoplanin is involved in oral tumorigenesis and may serve as a predictor for lymph node metastasis and poor clinical outcome.