Background & Aims: Interleukin-22 (IL-22) is a Th17-related cytokine within the IL-10 family and plays an important role in host defense and inflammatory responses in orchestration with other Th17 cytokines. IL-22 exerts its functions in non-immune cells as its functional receptor IL-22R1 is restricted in peripheral tissues but not in immune cells. It was recently found that IL-22 serves as a protective molecule to counteract the destructive nature of the T cell-mediated immune response to liver damage. However, it is currently unknown whether IL-22 has an effect on lipid metabolism in the liver. Methods: In this study, we demonstrate that IL-22 alleviates hepatic steatosis induced by high fat diet (HFD). Results: Administration of recombinant murine IL-22 (rmIL-22) was able to stimulate STAT3 phosphorylation in HepG2 cells and mouse liver. The activation of STAT3 by rmIL-22 was reduced by the over-expression of a dominant negative IL-22R1. Within hours after rmIL-22 treatment, the expression of lipogenesis-related genes including critical transcription factors and enzymes for lipid synthesis in the liver was significantly down-regulated. The levels of triglyceride and cholesterol in the liver were significantly reduced by long-term treatment of rmIL-22 in C57BL/6 and ob/ob mice fed with HFD. The HFD-induced increases of ALT and AST in ob/ob mice were ameliorated by rmIL-22 treatment. In addition, the expression of fatty acid synthase and TNF-α in the liver was decreased by long-term rmIL-22 administration. Conclusions: Collectively, these data indicate that IL-22, in addition to its known functions in host defense and inflammation, has a protective role in HFD-induced hepatic steatosis via its regulation on lipid metabolism in the liver. © 2010 European Association for the Study of the Liver.