Oncostatin M (OSM) is a multifunctional cellular regulator acting on a wide variety of cells, which haspotential roles in the regulation of gene activation, cell survival, proliferation and differentiation. Previousstudies have shown that OSM can induce morphological and/or functional differentiation and maturation ofmany tumor cells. However, the action of OSM on the induction of differentiation of human hepatocellularcarcinoma (HCC) has not been reported. Here, we investigated the effects of different concentrations of OSMon human HCC cell line SMMC-7721 growth, proliferation, cell cycling, apoptosis and differentiation in vitro.Cell growth was determined via MTT assay, proliferation by cell cycle analysis, apoptosis by flow cytometry,morphology by transmission electronic microscopy, and cell function by detection of biochemical markers.Our results demonstrated that OSM strongly inhibited the growth of SMMC-7721 cells in a dose-dependentmanner, associated with decreased clonogenicity. Cell cycle analysis revealed a decreased proportion of cells inS phase, with arrest at G0/G1. The apotosis rate was increased after OSM treatment compared to the control.These changes were associated with striking changes in cellular morphology, toward a more mature hepaticphenotype, accompanied by significant reduction of the expression of AFP and specific activity of γ-GT, withremarkable increase in secretion of albumin and ALP activity. Taken together, our findings indicate that OSMcould induce the differentiation and reduce cell viability of SMMC-7721 cells, suggesting that differentiationtherapy with OSM offers the opportunity for therapeutic intervention in HCC.