The aim of the present study was to evaluate the preventive role of genistein, a phytoestrogen with a wide variety of pharmacological effects, in an experimental non-alcoholic steatohepatitis (NASH) model.Thirty-six Sprague-Dawley rats were divided into three groups. Group 1 (control) received only a standard rat diet, group 2 (placebo) was given a high fat diet (HFD) plus 0.5 mL/day saline subcutaneously, and group 3 (genistein group) a HFD plus subcutaneous genistein injection at dose of 0.2 mg/kg/day for 6 weeks. All rats were killed after 6 weeks. Serum aminotransferases, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and plasma and liver malondialdehyde (MDA) levels were measured. Additionally, steatosis, ballooning degeneration and inflammation of the liver were examined histopathologically.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (P0.001 for each), plasma and liver tissue MDA and plasma TNF-alpha levels (P0.001,0.001,0.01, respectively) were found to be higher in the placebo group than in the control group. TGF-beta levels, however, were comparable in the placebo and control groups (P0.05). Histopathologically, steatosis, inflammatory cells per mm(2) and ballooning degeneration were significantly higher in the placebo group than in the control group (P0.001 for each). Nevertheless, AST and ALT (P0.05 for each), plasma and liver tissue MDA (P0.05 for each) and plasma TNF-alpha levels (P0.001) were significantly decreased in the genistein group compared to the placebo group. Histopathologically, steatosis (P0.05), inflammatory cells per mm(2) and ballooning degeneration (P0.01 for each) in the genistein group were also significantly lower than in the placebo group.Genistein, a strong antioxidant agent, significantly decreased the plasma TNF-alpha level and remarkably prevented the emergence of NASH by improving the biochemical and histopathological abnormalities via attenuating oxidative stress.