The E-cadherin-mediated cell adhesion system is frequently inactivated by multiple mechanisms and is involved in tumor progression in many types of cancer. Recently we have reported a novel cell membrane glycoprotein, dysadherin, which has an anti-cell-cell adhesion function and downregulates E-cadherin. Expressions of dysadherin and E-cadherin were investigated immunohistochemically in 91 patients with squamous cell carcinoma of the tongue to determine the correlation between the 2 molecules and their associations with the clinicopathologic features of the tumors and with patient survival. Dysadherin was expressed at the cell membranes of many cancer cells. Twenty-five percent of the tumors showed dysadherin immunopositivity in more than 50% of the cancer cells. Sixty-nine percent of the tumors showed reduced E-cadherin immunopositivity. There was an inverse correlation between dysadherin expression and E-cadherin expression (P = 0.0001). Increased dysadherin expression was significantly correlated with an infiltrative type of growth pattern (P = 0.001), high tumor-node-metastasis (TNM) stage (P = 0.024), and poor patient survival (P = 0.003). After adjusting for growth pattern, TNM stage, and other clinicopathologic features, increased dysadherin expression and reduced E-cadherin expression were both significant predictors of poor survival (P = 0.0006). Increased dysadherin expression is a significant indicator of poor prognosis in patients with squamous cell carcinoma of the tongue.