Fat accumulation in the liver involves an imbalance in the hepatic uptake of free fatty acids and their metabolism. Fat accumulation in the liver plays a critical role in the initiation of nonalcoholic steatohepatitis, which may progress to liver fibrosis and cirrhosis. The prevention of hepatic fat accumulation, therefore, may be effective therapy for nonalcoholic fatty liver disease. However, the effect of insulin sensitizing drugs on hepatic fat accumulation is still unclear. Here, we show that metformin, the most widely used insulin sensitizer, prevents liver fat accumulation induced by a high-fat diet. Male C57BL/6 mice weighing 18~20 g were grouped as follows for 8 weeks: mice chow diet, high-fat diet pair-fed control, and high-fat diet with metformin. Triglyceride and total cholesterol levels in plasma and liver were measured. AMP-activated protein kinase activity in liver were determined by Western blot. Expressions of SREBP1c and FAS in the liver were measured using RT-PCR. The high-fat diet increased body weight, abdominal fat mass, fat accumulation in the liver, and plasma total cholesterol, as well as liver triglyceride and total cholesterol levels, but plasma triglyceride levels were unchanged. Metformin decreased each of these measures. The high-fat diet decreased liver AMP-activated protein kinase activity as well as SREBP-1c and FAS expressions, and metformin reversed these changes. In conclusion, a high-fat diet induced visceral obesity and hepatic fat accumulation. Metformin prevented visceral obesity, hepatic fat accumulation, and reduced plasma total and LDL-cholesterol concentrations, potentially through modulating AMP-activated protein kinase activity and the expressions of SREBP-1C and FAS.