Prostaglandin E 2 (PGE 2 ) mediates a variety of innate and adaptive immunity through four distinct receptors: EP1-EP4. It has been suggested that each EP plays a unique and pivotal role in various disease conditions. We investigated the pathophysiological role of EP receptors in hepatic ischemia/reperfusion (I/R) injury. In this study, a 70% hepatic ischemic model was used in male C57BL/6 mice. Selective EP agonists were used to clarify the function of each PGE 2 receptor in I/R injury. Although all four receptors were expressed in the naΔ± Β¨ve liver, EP4 expression was significantly upregulated after hepatic I/R. Although EP1, 2, or 3 agonists did not show any protective effect on liver function, the EP4 agonist significantly inhibited hepatic I/R injury as determined by serological and histological analyses. Furthermore, the EP4 agonist downregulated the local expressions of several proinflammatory cytokines, chemokines, and adhesion molecules in the early phase of reperfusion. In contrast, it augmented the local expression of an anti-inflammatory cytokine, interleukin 10. Additionally, the neutrophil accumulation was also inhibited by EP4 agonist treatment. Finally, to confirm the therapeutic efficacy of the EP4 agonist in hepatic I/R injury, the nonischemic shunt liver was removed after 120 minutes of ischemia, resulting in the death of 86% of control mice within 48 hours. In sharp contrast, 80% of mice treated with the EP4 agonist survived. In conclusion, the PGE 2 -EP4 signaling pathway has an inhibitory role in hepatic I/R injury. An EP4 agonist effectively protects against ischemic injury. (HEPATOLOGY 2005;42:608-617.) H epatic ischemia/reperfusion (I/R) injury is the main cause of hepatic damage and is an inevitable event after liver resection and transplantation. 1,2 Favorable outcomes of liver transplantation have been increasing the need for hepatic grafts. To correct the imbalance between available organs and the number of patients waiting for grafts, the use of marginal organs which would otherwise be discarded or would be expected to lead to malfunction after transplantation may be required. I/R injury is a critical barrier to the use of these marginal organs and thus needs to be overcome. Therefore, despite recent improvements in liver preservation and surgical techniques, hepatic I/R injury remains an important clinical problem. Previous studies have revealed that the underlying mechanisms of hepatic I/R injury are considerably complex and that multiple factors are involved. The initial phase is associated with the generation of nontoxic oxygen species, the activation of Kupffer cells, and an initial response of neutrophil activation. Activated Kupffer cells release numerous metabolites that cause cellular damage, including superoxide radicals, nitric oxide, eicosanoids, proteases, and proinflammatory cytokines. Cytokines such as tumor necrosis factor β£ (TNF-β£); interleukin (IL)-1β€, -6, and -12; and interferon β₯ (IFN-β₯) and chemokines such as macrophage inflammatory protein 2 and KC have been pro-