Freshwater clam is traditionally used as a food and has been mentioned in ancient books to have a hepatoprotective effect. The hepatoprotective effect of freshwater clam extract was evaluated in the model of chronic hepatic fibrosis induced by carbon tetrachloride (CCl4). Male Sprague-Dawley rats were orally treated with freshwater clam extract (0.3, 0.6 and 1.5 g/kg of bw) or silymarin (0.2 g/kg of bw) along with the administration of CCl4 (0.5 ml/rat, 20% CCl4 in olive oil) for eight consecutive weeks. Blood samples were collected for assaying serum biochemical parameters. The livers were excised for evaluating peroxidation products and antioxidant substances, as well as the activities of antioxidant enzymes. Pathological histology was also performed. The data showed that supplementation of freshwater clam extract (0.6 g/kg bw) significantly reduced the serum levels of alanine aminotransferase and aspartate aminotransferase in rats treated with CCl4, and also decreased the thiobarbituric acid reactive substances, hydroxyproline and excessive inflammation in the livers of CCl4-treated rats. Histopathological analysis of the liver showed that freshwater clam extract (0.6 g/kg bw) markedly reduced the injury score of the fibrosis induced by CCl4 in rats. The data suggest that oral administration with freshwater clam extract might provide a novel and alternative approach for treating chronic liver failure.