Abstract: The study aimed to investigate the effect of pegylated interferon alpha (Peg IFN α2a), standard interferon alpha (Std IFN α2a) and silymarin in liver fibrosis induced in rats by chronic treatment with carbon tetrachloride (CCl4). Rats were divided into 9 groups (n = 7 per group). Group 1 received olive oil (0.5 mL kg-1, p.o. twice weekly) for 8 weeks followed by saline for 4 weeks (normal control). The remaining 8 groups received CCl4 (0.5 mL kg-1, p.o.) twice weekly for 8 weeks, followed by saline (CCl4 control), Std. IFN α2a (1.5 or 3 MIU kg-1, s.c., 3 times per week), Peg IFN α2a (1 or 2 μg kg-1, s.c., once per week), silymarin (100 mg kg-1 day-1, p.o.) alone or combined with either Peg IFN α2a (1 μg kg-1) or Std. IFN α2a (1.5 MIU kg-1), respectively for 4 weeks. At the end of the experiment, blood samples were collected and livers were isolated for biochemical and histological assessment of markers related to liver fibrosis. Administration of CCl4 resulted in increases in liver function tests, liver lipid peroxides and hydroxyproline contents coupled with decrease in total protein and liver content of reduced glutathione. Administration of Peg IFN α2a or silymarin alone or combined together attenuated CCl4-induced changes. On the other hand, using Std. IFN was not coupled by significant improvement in CCl4-induced changes, an effect that was reversed by its combination with silymarin. In conclusion, administration of Peg IFN, silymarin or their combination can limit hepatocellular fibrosis caused by chronic CCl4 administration; whereas, the effects of Std. IFN are only evident when combined with silymarin.