BACKGROUND/AIMS Fibrosis and cirrhosis are common complications of chronic liver diseases. An imbalance between fibrogenesis and fibrolysis results in scarring of the liver parenchyma. We aimed to investigate the possible antifibrotic effectiveness of a newly modified interferon molecule peginterferon alpha2b (PEG-IFNalpha2b) which has better antiviral activity, and ursodeoxycholic acid (UDCA). METHODOLOGY Liver fibrosis was established on 60 male Sprague Dawley rats with CCl4 in 12 weeks. After cessation of CCl4 Group I was left for spontaneous recovery. Group II was treated with PEG-IFN 1.5 microg/kg/week, Group III with UDCA 25 mg/kg/day and Group IV with combination of both drugs. All rats were killed at week 16. Histopathologic fibrosis scores, tissue hydroxyproline, TIMP-1 and MMP-13 levels were determined. Hepatic stellate cell apoptosis was detected by dual staining with TUNEL technique and anti-alpha smooth muscle actin. RESULTS Fibrosis scores were lower in Group II, III and IV than Group I (p<0.05 for group I vs. II and III; p<0.01 for group I vs. IV). Tissue hydroxyproline levels were significantly decreased in Group II, III and IV when compared to Group I (p<0.05 for group I vs. II, p<0.01 for group I vs. III and IV). Lower liver TIMP-1 and higher MMP-13 levels were measured in Group II, III, and Group IV than Group I (p<0.01 for TIMP-1 and p<0.01, for MMP). Activated HSC apoptosis was significantly increased in Group II, III and IV when compared to Group I (p<0.01, for all). There was significantly higher apoptosis in Group II than Group III and IV (p<0.01). CONCLUSION Treatment with both PEG-IFNalpha2b and UDCA improved CCl4 induced rat liver fibrosis. Significantly higher effects were obtained using these agents in combination.