E-cadherin is a major cell adhesion molecule implicated as a potent tumor suppressor, which is frequently altered in human tumors including hepatocellular carcinoma. Here, we report that hepatitis C virus Core downregulates E-cadherin expression at the transcription level. This effect was abolished after treatment of 5'-Aza-2'dC, a specific inhibitor of DNA methyltransferase (DNMT). In addition, this repression was strongly correlated with hypermethylation of CpG islands of E-cadherin promoter via concerted action of both DNMT1 and 3b in Core-expressing cells. The decreased E-cadherin expression results in dramatic morphological changes in Core-expressing cells. In addition, Core-expressing cells aggregate poorly in suspension culture, reflecting their altered cell-cell interactions. The biological significance was further demonstrated by the increased collagen invasion ability of Core-expressing cells. Therefore, our finding suggests that Core plays a role in hepatocellular carcinogenesis by favoring cell detachment from the surrounding cells and migration outside of the primary tumor site.