Multipotent mesenchymal stromal (MS) cells from adult bone marrow are a cell population that can be expanded to large numbers in culture. MS cells might be differentiated toward hepatocytes in vitro and thus are promising candidates for therapeutic applications in vivo. The efficacy of bone marrow-derived MS cells versus hepatocytes to contribute to liver regeneration was compared in a rat model of prolonged toxic hepatic injury. Liver damage was induced by injection of carbon tetrachloride (CCl4) or allyl alcohol (AA) with and without retrorsine (R) pretreatment. MS cells or hepatocytes of wild-type F344 rats were injected into dipeptidyl peptidase IV (DPPIV)-deficient syngeneic rats. Hepatocyte chimerism was higher after intraportal hepatocyte transplantation in the R/AA group (mean maximal cluster size [MCS] = 21 cells) compared with the R/CCl4 treatment group (MCS = 18). No hepatocyte engraftment was outlined following post-transplant CCl4 injection only, whereas mere AA injection resulted in small clusters of donor-derived hepatocytes (MCS = 2). Intraparenchymal injection of hepatocytes was associated with a MCS = 11 after R/AA treatment and a MCS = 6 after AA administration alone. Redistribution of MS cells to the liver was shown after intraportal and intraparenchymal injection. In contrast to hepatocyte transplantation, however, donor-derived DPPIV-positive cells could not be demonstrated in any recipient after MS cell transplantation. Data from the present study indicate that a well-defined population of MS cells obtained according to established standard protocols does not differentiate into hepatocytes in vivo when transplanted under regenerative conditions, in which the application of hepatocytes results in stable hepatic engraftment.