Concanavalin A (Con A) induces hepatitis in mice, which is an established model of acute immune-mediated hepatitis. Real-time PCR analysis revealed that mRNAs for prostaglandin E₂ (PGE₂) synthetic enzymes and PGE₂ receptor subtype EP4 were up-regulated in the liver of wild-type mice after Con A administration. In this study, we attempted to clarify the role of the PGE₂-EP4 system in Con A-induced hepatitis. After Con A administration, serum transaminase (AST and ALT) levels in EP4-deficient mice were significantly higher than those in wild-type mice. Accordingly, histological examination of the liver revealed significant increase in the size of necrotic areas in EP4-deficient mice compared with that in wild-type mice. To evaluate whether EP4 agonists protect the liver, an EP4 agonist ONO-4819CD was administered into wild-type mice before Con A administration. ONO-4819CD prominently decreased serum transaminase levels after Con A administration, suggesting the liver protective effect of EP4 agonists in Con A-induced hepatitis. These results indicate that the PGE₂-EP4 system plays a liver protective role in Con A-induced hepatitis and suggests that EP4 agonists are promising therapeutic candidates for the treatment of immune-mediated hepatitis.