Insulin-like growth factor II (IGF-II) mRNA expression is developmentally regulated in liver tissue. We previously observed the reexpression of fetal IGF-II mRNAs in human primary liver cancer and in surrounding cirrhotic tissue. In order to determine the steps of liver cancer progression where the activation of IGF-II fetal mRNAs occurs, we analyzed IGF-II mRNA expression during hepatocarinogenesis in transgenic mice carrying an antithrombin III-SV40 early region hybrid gene. The comparative analysis of mRNAs encoding IGF-II and other differentiation-associated proteins, as well as histological analysis, indicate that the reexpression of fetal IGF-II mRNAs takes place in specific steps of liver cancer progression, both in early pretumorous lesions and in well-differentiated hepatocellular carcinomas.