The hepatitis B virus x (HBx) protein has been implicated in the pathogenesis of HBV-associated hepatocellular carcinoma (HCC). The mechanisms of HBx involved in epigenetic changes during hepatocarcinogenesis are still obscure. We report here that microRNA-200c (miR-200c) was downregulated in HBV-expressing HCC cells and it targeted DNMT3A directly.. In addition, an inverse correlation between miR-200c and DNA methyltransferase 3A (DNMT3A) was founded in HBV-induced HCC tissues. HBV-induced downregulation of miR-200c upregulated DNMT3A expression, and then resulted in promoter hypermethylation of tumor-related genes in HCC. Our data supplied an epigenetic insight into HBV-induced HCC and identified a potential miRNA-based targeted approach for treating HBV-related HCC.