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Background: MicroRNA-122 (miR-122), a pivotal liver-specific miRNA, is frequently repressed in hepatocellular carcinoma (HCC) and associated with poor prognosis. Long non-coding RNA (lncRNA) HOTAIR has been proved to function as an oncogene in multiple cancers including HCC. However, the relationship between HOTAIR and miR-122 in HCC remains largely unknown. Methods: We investigated the function of HOTAIR and miR-122 in HCC cell models and a xenograft mouse model. The regulatory network between HOTAIR and miR-122 was further detected following overexpression or knockdown of HOTAIR. DNA methylation status of miR-122 promoter region, as well as expression levels of DNMTs, EZH2 and Cyclin G1 were analyzed. Findings: In this study, we found that HOTAIR was highly expressed whereas miR-122 was suppressed in HCC, and HOTAIR negatively regulated miR-122 expression in HCC cells. Furthermore, knockdown of HOTAIR dramatically inhibited HCC cell proliferation and induced cell cycle arrest in vitro and suppressed tumorigenicity in vivo by upregulating miR-122 expression. Mechanistically, a CpG island was located in the miR-122 promoter region. HOTAIR epigenetically suppressed miR-122 expression via DNMTs-mediated DNA methylation. Moreover, HOTAIR upregulated DNMTs expression via EZH2. In addition, suppression of miR-122 induced by HOTAIR directly reactivated oncogene Cyclin G1 expression. Collectively, our results suggest that HOTAIR epigenetically suppresses miR-122 expression via DNA methylation, leading to activation of Cyclin G1 and promotion of tumorigenicity in HCC, which provide new insight into the mechanism of HOTAIR-mediated hepatocarcinogenesis via suppressing miR-122. Keywords: Hepatocellular carcinoma, LncRNA HOTAIR, microRNA-122, DNA methylation, Epigenetics