Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil‐dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL‐12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL‐18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL‐18 is up‐regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL‐18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL‐18 expression was up‐regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor‐κB (NF‐κB) and activator protein 1 (AP‐1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate biotin nick end‐labeling (TUNEL) staining, serum aminotransferase levels, and liver wet‐to‐dry weight ratios. In mice treated with neutralizing antibody to IL‐18, ischemia/reperfusion‐induced increases in CXC chemokine expression, activation of NF‐κB and AP‐1, and apoptosis were greatly reduced. Furthermore, under blockade of IL‐18, anti‐inflammatory cytokines such as IL‐4 and IL‐10 were greatly up‐regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL‐18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL‐18 is required for facilitating neutrophil‐dependent hepatic ischemia/reperfusion injury through suppressing anti‐inflammatory cytokine expression. (HEPATOLOGY 2004;39:699–710.)