Objective and Design: The ability of interleukin-4 (IL-4) to modulate activation of the transcription factors, NF-κB and STAT6, reduce proinflammatory cytokine expression and protect against liver injury induced by ischemia/ reperfusion was assessed.¶Materials and Subjects: C57BL/6 mice underwent 90 minutes of partial hepatic ischemia followed by 1 or 8 h of reperfusion with or without intravenous administration of 1 μg (0.5 μg just prior to ischemia, 0.5 μg at reperfusion) recombinant murine IL-4. Liver expression of TNFα mRNA was determined by RT-PCR. Activation of NF-κB and STAT6 in liver nuclear extracts was assessed by mobility shift assay.¶Results: Hepatic ischemia/reperfusion increased hepatic expression of tumor necrosis factor-α (TNFα), induced significant neutrophil accumulation and liver injury. Treatment with IL-4 greatly suppressed liver TNFα mRNA expression, neutrophil accumulation and liver injury. IL-4 had no effect on liver NF-κB activation, but greatly increased the activation of STAT6.¶Conclusions: The data suggest that STAT6 activation by IL-4 may be responsible for the protective effects of this cytokine.