While CD8-subsets activate hepatic-fibrosis; natural-killer (NK) cells exhibit anti-fibrotic activity. Glatiramer-acetate (GA) is immune-modulator for multiple-sclerosis. We assessed the potential impact of GA on mouse hepatic-fibrogenesis. Methods: Hepatic-fibrosis was induced in C57Bl/6-mice by intra-peritoneal (IP) administration of carbon-tetrachloride (CCl₄) for 6-weeks. Within the last 2-weeks, animals were also treated either with GA (200micrograms/day) IP or medium, and were compared to naive and fibrotic mice. Eight-animals were included in each group. Results: GA markedly attenuated fibrosis. GA markedly attenuated fibrosis without altering reactive-oxygen-species production. By morphometric measurement of Sirius red-stained tissue sections: the relative fibrosis area decreased from 5.28%±0.32 in the untreated CCl₄ group, compared with 2.01±0.28 in CCl₄-treated animals that also received GA (p<0.0001), compared with 0.38±0.07 in naive mice. Alpha-smooth-muscle-actin immunoblotting and mRNA expression revealed a similar pattern. Serum aminotransferase and necro-inflammatory-score were markedly elevated, to the same extent in both CCl₄-treated groups. Fibrosis induction was associated with a significant increase in CD8-subsets and a decrease in CD4-T-cells. Following GA-treatment, however, NK content, CD4+CD25+FoxP3+ cells, hepatic expression of tumor-necrosis-factor-related-apoptosis-inducing-ligand (TRAIL) as well as apoptosis of hepatic-stellate- cells (HSC) were all increased. Serum IL-10 levels markedly rose, whereas IL-4 fell. The in vitro activation of human HSC co-cultured with HCV-derived peripheral- blood-lymphocytes decreased when lymphocytes were pre incubated with GA before co-culture. Conclusion: In an animal model of hepatic fibrosis, GA has an anti-fibrotic effect associated with decreased CD8 cells and reduced serum IL-4 levels and increased NK cells, CD4+ CD25+FoxP3+ cells, TRAIL and elevated serum IL-10 levels.