The aims of this study were to determine if combining features of a western lifestyle in mice with trans-fats in a high fat diet, high fructose corn syrup in the water and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Methods: Male C57BL/6 mice fed ad libitum high fat chow containing trans-fats (partially hydrogenated vegetable oil) and relevant amounts of a high fructose corn syrup equivalent (HFCS) for 1 to 16 weeks were compared to mice fed standard chow or mice with trans-fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. Results: By 16 weeks, trans-fat fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma ALT levels increased as did liver TNF and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 weeks respectively. Plasma insulin, resistin and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans-fats with lard established that trans-fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity and impaired insulin sensitivity. Conclusions: Combining risk factors for the metabolic syndrome by feeding mice trans-fats and high fructose corn syrup induced histologic features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans-fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation.