The current study investigated the combined effects of feeding a high fat/high sucrose (HF/HS) diet to sedentary rodents. Accordingly, male Wistar rats were fed chow or a diet in which 32% of calories were derived from corn oil fat and 48% of calories from sucrose for 3 weeks. Feeding continued during an additional 3-week period of hindlimb unloading (HU). Subsequently, blood samples were collected for determination of circulating leukocyte counts, insulin levels and portal vein endotoxin. Inflammation, necrosis and steatosis were assessed in formalin-fixed liver sections. No biochemical or histological evidence of injury was observed in control rats fed chow or HF/HS. HU increased circulating neutrophils, and resulted in hyperinsulinemia. Mild hepatic fat accumulation and minimal focal necro-inflammation were observed in this group. Feeding HF/HS during HU exacerbated hyperinsulinemia, hepatic steatosis, Kupffer cell content and cytokine expression. Portal endotoxemia was noted in HU rats, but was not influenced by HF/HS diet. On the other hand, feeding HF/HS significantly enhanced lipid peroxidation end products in liver of HU rats by approximately 3-fold compared to chow-fed rats. In summary, these findings demonstrate that feeding a high calorie diet potentiates steatosis and injury in sedentary HU rats. Mechanisms underlying enhanced injury most likely involved lipid peroxidation. Importantly, these findings suggest that dietary manipulation combined with physical inactivity can be used to model steatohepatitis.