OBJECTIVE Activin A is an autocrine negative regulator of DNA synthesis in rat hepatocytes and is expressed in remnant liver after partial hepatectomy. To determine the role of activin A in liver regeneration, the effects of exogenous follistatin, which blocks the action of activin A, were examined. METHODS Human recombinant follistatin was infused into the portal vein immediately after 70% hepatectomy. Changes in body weight, remnant liver weight, liver regeneration rate, and nuclear bromodeoxyuridine labeling were measured. RESULTS In control rats, nuclear labeling was observed at 24 hours and peaked at 36 hours after the hepatectomy. In follistatin-treated rats, nuclear labeling was first observed after 18 hours and was significantly (P < 0.05) greater than that in control rats at 24 hours. In follistatin-treated rats, both remnant liver weight and liver regeneration rate were significantly greater at 120 hours. Serum concentrations of albumin and glucose remained reduced for up to 120 hours in control rats but recovered in follistatin-treated rats. CONCLUSIONS A single administration of follistatin accelerates the initial round of DNA synthesis after partial hepatectomy. Activin A produced in remnant liver may exert tonic inhibitory effect on liver regeneration. Follistatin may be useful as a potential therapeutic agent to promote liver regeneration.