BACKGROUND: Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. The objective was to determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease. METHODS: E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance. RESULTS: pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (p=0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (p=0.005) in univariate and multivariate analysis. CONCLUSION: These data suggest that loss of E-cadherin expression is associated with increased lymphogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx. Level of evidence: 2b.