Autoimmune hepatitis is a worldwide health problem and significant cause of mortality. However, the disease etiology is largely unknown, which accounts for ineffective treatment and uncontrolled disease progression. Recently, interleukin-17 (IL-17) family of cytokines has been implicated as critical players in a variety of inflammatory diseases. Among them, IL-17C has been highlighted to be essential in mucosal immunity and autoimmune responses. In this study, we demonstrated the functional importance of the IL-17C/IL-17RE axis in Con A–induced hepatitis, since the liver damage was dramaticlly suppressed in IL-17C-deficient and IL-17RE-deficient mice. Elevated IL-17C expression was detected in liver samples of both human and mouse autoimmune hepatitis. IL-17C, produced by hepatocytes, and its specific receptor IL-17RE on liver-resident T cells were both found to be required in Con A–induced liver damage. Mechanistically, IL-17C augmented the expression of IL-2 by intrahepatic CD4+ T cells to promote NK cell activation and liver damage. To our knowledge, our findings thus for the first time defined the indispensable role of IL-17C/IL-17RE in autoimmune hepatitis; this axis may serve as a novel drug target for the treatment of this disease.