introduction and aims: Interferon-α (IFN) has shown potential benefits in patients with hepatocellular carcinoma (HCC), and these effects may be mediated by inhibiting cancer cell proliferation. However, the detailed mechanisms underlying the anti-proliferative effects of IFN remain obscure. In this study, we evaluate the role of the novel oncogenic microRNA (miRNA) miR-155 in the anti-proliferative effects of pegylated interferon-α (PEG-IFN) on HCC cells. methods: The effects of PEG-IFN on HepG2 cell proliferation, migration and invasion were determined using the MTT assay, flow cytometry analysis and the Transwell assay, respectively. Reverse transcription quantitative polymerase chain reaction was used to analyze miR-155 expression. The levels of proteins involved in Wnt/β-catenin signal transduction were determined by western blot analysis and immunofluorescence staining. Mimics of miR-155 were transfected into HepG2 cells to assess the role of miR-155 in the PEG-IFN-induced anti-proliferative effect. results: PEG-IFN significantly inhibited the proliferation, migration and invasion of HepG2 cells in a dose-dependent manner by inhibiting cell cycle progression. In parallel with reduced cell proliferation, migration and invasion, miR-155 was efficiently downregulated by PEG-IFN in a dose-dependent manner. Moreover, the transfection of miR-155 decreased the inhibitory effect of PEG-IFN on HepG2cell proliferation, migration and invasion, as well as the downregulation of proteins in the Wnt/β-catenin pathway. conclusions: The anti-proliferative effects of PEG-IFN on HCC are at least partially attributable to the downregulation of miR-155.