Hepatic ischemia/reperfusion (I/R) injury associated with liver transplantation and hepatic resection is characterized by hepatocellular damage and a deleterious inflammatory response. In this study, we examined whether receptor for advanced glycation end product (RAGE) activation is linked to mechanisms accentuating inflammation on I/R in a murine model of total hepatic ischemia. Animals treated with soluble RAGE (sRAGE), the extracellular ligand‐binding domain of RAGE, displayed increased survival after total hepatic I/R compared with vehicle treatment. TUNEL assay and histologic analysis revealed that blockade of RAGE was highly protective against hepatocellular death and necrosis on I/R; in parallel, proliferating cell nuclear antigen was enhanced in livers of mice treated with sRAGE. Rapid activation of p38, p44/42, stress‐activated protein kinase and c‐Jun N‐terminal kinase mitogen‐activated protein kinases, signal transducer and activator of transcription‐3, and nuclear translocation of activator protein‐1 was evident at early times on I/R. In the remnants of sRAGE‐treated livers, however, activation of each of these signaling and transcription factor pathways was strikingly decreased. sRAGE‐treated remnants displayed enhanced activation of nuclear factor κB, in parallel with increased transcripts for the proregenerative cytokine, tumor necrosis factor‐α. In conclusion, these data suggest that RAGE modulates hepatic I/R injury, at least in part by activation of key signaling pathways linked to proinflammatory and cell death‐promoting responses. We propose that blockade of this pathway may represent a novel strategy to attenuate injury in hepatic I/R and to facilitate regeneration. (HEPATOLOGY 2004;39:422–432.)