Recent studies have demonstrated that n-3 polyunsaturated fatty acids ameliorate nonalcoholic fatty liver disease. Although eicosapentaenoic acid (EPA), one of the major components of n-3 polyunsaturated fatty acids, is widely used as an antilipidemic agent, its single efficacy for nonalcoholic steatohepatitis (NASH) remains unclear. As such, we aimed to evaluate the efficacy and safety of EPA on 23 biopsy-proven NASH patients in a pilot trial. Highly purified EPA (2700 mg/d) was administered for 12 months and efficacy was assessed by biochemical parameters and liver histology. All patients completed the treatment with no adverse events, indicating acceptable tolerance to the treatment. After 12 months, serum alanine aminotransferase levels were significantly improved (from 79±36 to 50±20 U/L), and serum free fatty acids, plasma soluble tumor necrosis factor receptor 1 and 2 levels, and serum ferritin and thioredoxin levels, which may reflect hepatic oxidative stress, were significantly decreased. Body weight, blood glucose, insulin, and adiponectin concentrations remained unchanged. Seven of the 23 patients consented to undergo posttreatment liver biopsy, which showed improvement of hepatic steatosis and fibrosis, hepatocyte ballooning, and lobular inflammation in 6 patients. In conclusion, EPA treatment seems to be safe and efficacious for patients with NASH, largely due to its anti-inflammatory and antioxidative properties. To confirm these results, appropriately powered, controlled trials are needed.