Liver injury induced by hepatic ischemia/reperfusion is characterized by activation of the transcription factor NF-κB, increased production of tumor necrosis factor-α (TNFα), liver neutrophil accumulation, and hepatocellular damage. Exogenous administration of interleukin-4 (IL-4) or IL-13 was recently shown to regulate this inflammatory injury in association with activation of signal transducer and activator of transcription-6 (STAT6). The objective of the present study was to determine whether STAT6 was required for the regulation of liver inflammation by IL-4 and IL-13. Wild-type and STAT6 knockout mice underwent 90 minutes of hepatic ischemia followed by 8 hours of reperfusion. Hepatic ischemia/reperfusion in wild-type and STAT6 knockout mice significantly increased (P < 0.05) NF-κB activation, serum levels of TNFα, liver accumulation of neutrophils [measured by myeloperoxidase (MPO) content], and hepatocellular damage [measured by serum alanine aminotransferase (ALT)] compared to sham controls. In wild-type mice, activation of STAT6 was not observed after ischemia/reperfusion. Administration of 1 μg of IL-4 or IL-13 at reperfusion reduced serum TNFα, liver neutrophil accumulation, and hepatocellular injury in wild-type mice. Treatment with IL-4 or IL-13 had no effect on liver NF-κB activation but significantly increased activation of STAT6. In STAT6 knockout mice, neither IL-4 nor IL-13 had any effect on TNFα, MPO, or ALT values, the regulatory effects of these cytokines being completely abolished. The data suggest that activation of STAT6 may regulate liver inflammatory injury.