Interleukin (IL)‐33 is a recently identified member of the IL‐1 family that binds to the receptor, ST2L. In the current study, we sought to determine whether IL‐33 is an important regulator in the hepatic response to ischemia/reperfusion (I/R). Male C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia, followed by up to 8 hours of reperfusion. Some mice received recombinant IL‐33 (IL‐33) intraperitoneally (IP) before surgery or anti‐ST2 antibody IP at the time of reperfusion. Primary hepatocytes and Kupffer cells were isolated and treated with IL‐33 to assess the effects of IL‐33 on inflammatory cytokine production. Primary hepatocytes were treated with IL‐33 to assess the effects of IL‐33 on mediators of cell survival in hepatocytes. IL‐33 protein expression increased within 4 hours after reperfusion and remained elevated for up to 8 hours. ST2L protein expression was detected in healthy liver and was up‐regulated within 1 hour and peaked at 4 hours after I/R. ST2L was primarily expressed by hepatocytes, with little to no expression by Kupffer cells. IL‐33 significantly reduced hepatocellular injury and liver neutrophil accumulation at 1 and 8 hours after reperfusion. In addition, IL‐33 treatment increased liver activation of nuclear factor kappa light‐chain enhancer of activated B cells (NF‐κB), p38 mitogen‐activated protein kinase (MAPK), cyclin D1, and B‐cell lymphoma 2 (Bcl‐2), but reduced serum levels of CXC chemokines. In vitro experiments demonstrated that IL‐33 significantly reduced hepatocyte cell death as a result of increased NF‐κB activation and Bcl‐2 expression in hepatocytes. Conclusion: The data suggest that IL‐33 is an important endogenous regulator of hepatic I/R injury. It appears that IL‐33 has direct protective effects on hepatocytes, associated with the activation of NF‐κB, p38 MAPK, cyclin D1, and Bcl‐2 that limits liver injury and reduces the stimulus for inflammation. (HEPATOLOGY 2012)