Liver mass is optimized in relation to body mass. Rat (r) and human (h) hepatocytes were transplanted into liver-injured immunodeficient mice and allowed to proliferate for 3 or 11 weeks, respectively, when the transplants stopped proliferating. Liver/body weight ratio was normal throughout in r-hepatocyte-bearing mice (r-hep-mice), but increased continuously in h-hepatocyte-bearing mice (h-hep-mice), until reaching approximately three times the normal m-liver size, which was considered to be hyperplasia of h-hepatocytes because there were no significant differences in cell size among host (mouse [m-]) and donor (r- and h-) hepatocytes. Transforming growth factor-beta (TGF-beta) type I receptor, TGF-beta type II receptor, and activin A type IIA receptor mRNAs in proliferating r-hepatocytes of r-hep-mice were lower than in resting r-hepatocytes (normal levels) and increased to normal levels during the termination phase. Concomitantly, m-hepatic stellate cells began to express TGF-beta proteins. In stark contrast, TGF-beta type II receptor and activin A type IIA receptor mRNAs in h-hepatocytes remained low throughout and m-hepatic stellate cells did not express TGF-beta in h-hep-mice. As expected, Smad2 and 3 translocated into nuclei in r-hep-mice but not in h-hep-mice. Histological analysis showed a paucity of m-stellate cells in h-hepatocyte colonies of h-hep-mouse liver. We conclude that m-stellate cells are able to normally interact with concordant r-hepatocytes but not with discordant h-hepatocytes, which seems to be at least partly responsible for the failure of the liver size optimization in h-hep-mice.