Transforming growth factor- (TGF-) functions as an antiproliferative factor for hepatocytes. However, for unexplained reasons, hepatocytes become resistant to TGF- signals and can proliferate despite the presence of TGF- during liver regeneration. TGF- is up-regulated during liver regeneration, although it is not known whether it is active or latent. TGF- activity may be examined by assessing Smad activation, a downstream signaling pathway. Smad pathway activation during liver regeneration induced by partial hepatectomy or CCl 4 injury was examined by assessing the levels of phospho-Smad2 and Smad2-Smad4 complexes. We found that Smad proteins were slightly activated in quiescent liver, but that their activation was further en-