We have previously shown that the administration of low doses of insulin-like growth factor-I (IGF-I) to CCl4-cirrhotic rats improves liver function and reduces fibrosis. To better understand the mechanisms behind the hepatoprotective effects of IGF-I, and to identify those genes whose expression is affected in cirrhosis and after IGF-1 treatment, we have performed differential display of mRNA analysis by means of polymerase chain reaction (PCR) in livers from control and CCl4-cirrhotic rats treated or not with IGF-I. We have identified 16 genes that were up- or down-regulated in the cirrhotic liver. IGF-I treatment partially normalized the expression of eight of these genes, including serine proteinase inhibitors such as serpin-2 and alpha-1-antichymotripsin, alpha-1-acid glycoprotein, and alpha-2u-globulin. Additionally, we show that IGF-I enhanced the regenerative activity in the cirrhotic liver, as determined by the increased expression of the proliferating cell nuclear antigen (PCNA). Finally, IGF-I treatment partially restored the expression of growth hormone receptor (GHR) and the levels of global genomic DNA methylation, which are reduced in human and experimental cirrhosis. Taken together, our observations confirm the hepatoprotective effects of IGF-I, and suggest that this action can be exerted in part through the normalization of liver gene expression, growth hormone (GH) responsiveness and global genomic DNA methylation.