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In patients with early head and neck squamous-cell carcinoma (HNSCC), occult lymph node metastasis is difficult to predict by clinical or pathological parameters. Such parameters however are necessary to select patients either for elective neck dissection or the sentinel lymph node procedure. The membrane glycoprotein podoplanin is normally expressed in lymphatic endothelial cells. Recently, expression of podoplanin by cancer cells was demonstrated to promote tumor cell motility and tumor lymphangiogenesis in vitro. The value of cancer cell-expressed podoplanin was to be determined as a predictive marker for sentinel lymph node (SLN) metastasis in early HNSCC of the oral cavity and oropharynx. 120 patients with HNSCC of the oral cavity and oropharynx undergoing a SLN biopsy were enrolled in this prospective clinical trial of sentinel lymph node biopsy. Cancer cell-expressed podoplanin was determined by immunohistochemistry using tissue microarrays. Podoplanin expression was quantified by the Intensity Reactivity Score (IRS) and categorized into expression and non-expression. SLN examination revealed occult metastasis in 45 patients (37.5%). Twenty nine of 120 (24.2%) primary HNSCC showed podoplanin expression. Podoplanin expression correlated significantly with sentinel lymph node metastasis (p=0.029) and remained a significant predictor for lymph node status even after controlling for tumor stage (p=0.028). As a predictive marker for SLN metastasis however, podoplanin expression reached a sensitivity of a mere 36% and a specificity of 83%. Podoplanin expression is associated with metastasis to lymph nodes in vivo. Podoplanin immunohistochemistry in early HNSCC of the oral cavity and oropharynx may help to select patients for the SLN procedure and to identify patients with increased risk for presence of occult lymph node metastasis in the neck.