Ischemia/reperfusion injury of the liver requires the participation of proinflammatory cytokines, chemokines, and adhesion molecules, many of which are regulated by the transcription factor nuclear factor κB (NFκB). The anti-inflammatory cytokine, interleukin-10 (IL-10) affects inflammatory reactions, at least in part, through inhibitory effects on the transcription factor, NFκB. The objective of the current study was to determine whether IL-10 could suppress hepatic ischemia/reperfusion-induced NFκB activation and the ensuing inflammatory liver injury. C57BL/6 mice underwent partial hepatic ischemia and reperfusion with or without intravenous injections of recombinant murine IL-10. Hepatic NFκB activation was induced in a time-dependent fashion. IL-10 suppressed NFκB activation as well as messenger RNA expression of tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-2 (MIP-2). In addition, IL-10 reduced serum levels of TNF-α and MIP-2. Hepatic neutrophil recruitment, liver edema, and hepatocellular injury were all significantly reduced by IL-10. The data suggest that IL-10 protects against hepatic ischemia/reperfusion injury by suppressing NFκB activation and subsequent expression of proinflammatory mediators.