To examine the effect of osteopontin inhibition by tranilast on liver fibrosis, four groups of rats were used throughout this study. Group I (Control group): rats received the solvent. Liver fibrosis was induced in Groups II, III, and IV by thioacetamide (TAA; 200mg/kg, ip) twice weekly for 6 weeks. Group II served as (TAA group). Groups III and IV (Treatment groups): rats were given tranilast for 6 weeks after TAA discontinuation. Liver osteopontin (OPN), transforming growth factor-β (TGF-β1), tumor necrosis factor alpha (TNF-α), alpha-smooth muscle actin (ɑ-SMA)), reduced glutathione (GSH), superoxide dismutase (SOD) and lipid peroxidation (MDA) were measured. Additionally, expression of α-smooth muscle actin (SMA) and caspase (Cas)-3 were assigned immunohistochemically. Treatment with tranilast prevented the development of hepatic fibrosis and the activation of stellate cells, and down-regulated the expression of genes for osteopontin and osteopontin-target molecules, including TGF-β and TNF-α and α-SMA.Tranilast significantly decreased MDA and increased levels of GSH, and SOD. Our findings suggest that targeting osteopontin with tranilast represents a new mode of therapy for liver fibrosis.