Autoimmune hepatitis (AIH) is an inflammatory disease of the liver. Liver X receptors (LXRs), including the α and β isoforms, are previously known for their anti-inflammatory activities. The goal of this study is to determine whether and how LXR plays a role in AIH. LXRα gain-of-function and loss-of-function mouse models were used, in conjunction with the concanavalin A (ConA) model of T-cell mediated hepatitis. We first showed that the hepatic expression of LXRα was decreased in the ConA model of hepatitis and in human patients with AIH. In the ConA model, we were surprised to find that activation of LXRα in the constitutively activated VP-LXRα whole-body knock-in () mice exacerbated ConA-induced AIH, whereas the mice showed attenuated ConA-induced AIH. Interestingly, hepatocyte-specific activation of LXRα in the fatty acid binding protein-VP-LXRα transgenic mice did not exacerbate ConA-induced hepatitis. Mechanistically, the sensitizing effect of the allele was invariant natural killer T (iNKT)-cell dependent, because the sensitizing effect was abolished when the allele was bred into the NKT-deficient background. In addition, LXRα-enhanced ConA-induced hepatitis was dependent on interferon gamma. In contrast, adoptive transfer of hepatic iNKT cells isolated from mice was sufficient to sensitize mice to ConA-induced AIH. Activation of LXRα sensitizes mice to ConA-induced AIH in iNKT and interferon gamma-dependent manner. Our results suggest that LXRα plays an important role in the development of AIH.