BACKGROUND: Umbilical cord mesenchymal stem cells (UC-MSCs) have made certain curative effect on hepatic failure, but little is reported on the effect of hepatic failure patient's serum microenvironment on UC-MSCs differentiation ability. OBJECTIVE: To investigate the effect of hepatic failure patient's serum on the differentiation of umbilical cord mesenchymal stem cells into hepatic cells. METHODS: UC-MSCs were isolated by tissue adherent method and the cell morphology and phenotype identified by microscope and flow cytometry. Alpha-MEM media with serum before/after plasmapheresis were used to culture the hirdgeneration of UC-MSCs, and regular fetal bovine serum culture medium acted as control group. Inverted microscope was used to observe the cell morphology in three groups. Immunohistochemical method was used to measure expression level of alpha fetoprotein, albumin and cytokeratin 18. RESULTS AND CONCLUSION: A great amount of high-purity UC-MSCs could be obtained using tissue adherent method, which highly expressed CD44, CD73, CD90, CD10, but did not express CD45. Hepatic failure patient's serum could change the morphology of UC-MSCs and induce UC-MSCs to express alpha fetoprotein, albumin and cytokeratin 18. The positive expression of alpha fetoprotein, albumin and cytokeratin 18 was significantly increased after plasmapheresis (P < 0.05). To conclude, hepatic failure patient's serum after plasmapheresis exert more benefits to induce UC-MSCs to differentiate into hepatic cells than that before plasmapheresis.