Nonalcoholic fatty liver disease (NAFLD) is a common disease of chronic liver diseases. Peroxisome proliferator-activated receptor a (PPARa) has been implicated to play important roles in the development of the disease. Beyond its effects on lipidmetabolisms, PPARa activation in the vascular system has emerged as an attractive therapeutic potential for NAFLD, although its actions in the microcirculatory system are not fully understood. In this study, we investigated the effects of fenofibrate, a PPARa synthetic agonist, on hepatic microcirculation in a high-fat diet (HFD)-induced fatty liver in mice. In vivo imaging analysis revealed the adverse effects of HFDon hepatic vasculature with narrowing of hepatic sinusoids and hepatic microcirculatory perfusion. Oxygen tension was significantly decreased in portal venules, while NADH autofluorescence in hepatocytes was greatly elevated. Fenofibrate treatment remarkably improved microvascular patency, tissue oxygenation and redox states in the affected liver. These results suggest beneficial roles of PPARa activated by fenofibrate on the regulation of both lipid metabolisms and microvascular environments of oxygen metabolism in HFD-induced fatty liver.