Loss of T-cadherin expression has been reported in a number of human cancers. We previously reported that T-cadherin re-expression suppressed cell growth and motility in glioma. Here, we report that the T-cadherin expression was significantly decreased in human hepatocellular carcinoma (HCC) compared to adjacent normal liver. In addition, T-cadherin expression in HCC with metastasis was significantly lower than in HCC without metastasis. To determine the mechanism underlying the reduced T-cadherin expression in HCC, we examined T-cadherin promoter methylation. We found that methylation of the T-cadherin promoter was present in 40% of HCC, but absent in all adjacent liver tissues. In the HCC with T-cadherin promoter methylation, the T-cadherin expression was significantly decreased compared to HCC without methylation. To provide a functional link between T-cadherin promoter methylation and T-cadherin growth regulation, we used the HepG2 hepatoma cell line that exhibits T-cadherin promoter methylation. Treatment of HepG2 cells with the demethylating agent 5-aza-2-deoxycytidine resulted in increased T-cadherin expression and reduced cell proliferation. These results demonstrate that the T-cadherin down-regulation by promoter methylation is associated with the development and progression of HCC, and suggest that T-cadherin is an important tumor suppressor in liver cancer.