Background & Aims: The hepatitis B virus X protein (HBx) has been implicated as an oncogene in both epigenetic modifications and genetic regulation during hepatocarcinogenesis, but the underlying mechanisms are not entirely clear.Long non-coding RNAs (lncRNAs), which regulate gene expression with little or no protein-coding capacity, are involved in diverse biological processes and in carcinogenesis.We asked whether HBx could promote hepatocellular carcinoma (HCC) by regulating the expression of lncRNAs.Methods & Results: In this study, we investigated the alteration in expression of lncRNAs induced by HBx using microarrays and real-time quantitative PCR.Our results indicate that HBx transgenic mice have a specific profile of liver lncRNAs compared with wild-type mice.We identified an lncRNA, down-regulated expression by HBx (termed lncRNA-Dreh), which can inhibit HCC growth and metastasis in vitro and in vivo, act as a tumor suppressor in the development of HBV-HCC.LncRNA-Dreh could combine with the intermediate filament protein vimentin and repress its expression, and thus further change the normal cytoskeleton structure to inhibit tumor metastasis.We also identified a human ortholog RNA of Dreh (hDREH) and found that its expression level was frequently downregulated in HBV-related HCC tissues in comparison with the adjacent noncancerous hepatic tissues, and its decrement significantly correlated with poor survival of HCC patients.Conclusion: Our findings support a role of lncRNA-Dreh in tumor suppression and survival prediction in HCC patients.Our discovery contributes to a better understanding of the importance of the deregulated lncRNAs by HBx in HCC and provides a rationale for the potential development of lncRNA-based targeted approaches for the treatment of HBV-related HCC.