Activin A, a member of the transforming growth factor- control superfamily, is constitutively expressed in hepatocytes and regulates liver mass through tonic inhibition of hepatocyte DNA synthesis. Follistatin is the main biological inhibitor of activin bioactivity. These molecules may be involved in hepatic fibrogenesis although defined roles remain unclear. We studied activin and follistatin gene and protein expression in cultured rat hepatic stellate cells (HSC) and in rats given carbon tetrachloride (CCl₄) for eight weeks and examined the effect of follistatin administration on the development of hepatic fibrosis. In activated HSC, activin mRNA was upregulated with high expression levels while follistatin mRNA expression was unchanged from baseline. Activin A expression in normal lobular hepatocytes redistributed to peri-septal hepatocytes and smooth muscle actin positive HSC in fibrotic liver. A 32% reduction in fibrosis, maximal at week 4, occurred in CCl₄-exposed rats treated with follistatin. Hepatocyte apoptosis decreased by 87%, maximal at week 4, during follistatin treatment. In conclusion, activin is produced by activated HSC in vitro and in vivo. Absence of simultaneous upregulation of follistatin gene expression in HSC suggests that HSC-derived activin is biologically active and unopposed by follistatin. Our in vivo and in vitro results demonstrate that activin mediated events contribute to hepatic fibrogenesis and that follistatin attenuates early events in fibrogenesis by constraining HSC proliferation and inhibiting hepatocyte apoptosis.