Chimeric mice with repopulated human hepatocytes are widely used for drug development research. HepaRG cell line is a naturally immortalized human liver cell line with progenitor properties and inducible bipotent differentiation capability. It would be useful if HepaRG cells could repopulate damaged livers severe, combined immunodeficient × beige (SCID/bg) mice and exhibit special human hepatic features. After inducing mouse hepatocyte apoptosis with an antimouse agonistic Fas monoclonal antibody (Jo2 mAb), HepaRG cells with bipotent differentiation capability were repopulated in SCID/bg mouse livers. HepaRG cells were transplanted intrasplenically into SCID/bg mice treated with 0.2 mg/kg Jo2 mAb once a week for 10 weeks. Human hepatocyte repopulation was characterized by immunohistochemistry for human serum albumin (HSA), Hep Par1, and CK18 and by immunofluorescence staining for HSA. Human albumin mRNA was detected by reverse-transcription polymerase chain reactions. HSA levels were quantified by Western blotting and enzyme-linked immunosorbent assays. Our results showed that HepaRG cell engraftment protected mice from the effects of Jo2 mAb-mediated liver hemorrhage and hepatocyte apoptosis. At 2 weeks after transplantation, increase concentrations of HSA were detected in recipient blood and liver. At 12 weeks after transplantation, approximately 15%-20% of mice showed livers repopulated with human hepatocytes. In conclusion, normal SCID/bg mice were suitable recipients for HepaRG cell transplantation when induced with Jo2 mAb. This chimeric mouse model with HepaRG cells could serve as a useful model for in vivo studies of drug metabolism and hepatitis virus infections.