Egr-1 is a transcription factor that regulates genes involved in inflammation, innate and adaptive immunity, coagulation and wound-healing; however, little is known about the role of Egr-1 in acute liver injury. Here, we tested the hypothesis that Egr-1 is involved in acute liver injury induced by galactosamine/lipopolysaccharide (GalN/LPS). GalN/LPS exposure bi-phasically increased hepatic egr-1 mRNA accumulation at 1h and again at 4-5.5h after treatment in wild type mice. Within 4-5.5h after GalN/LPS exposure, wild type mice exhibited histological evidence of hepatocyte injury, cell death, and extensive areas of hemorrhage, as well as increased plasma ALT activities. In contrast, these parameters were largely attenuated in egr-1 -/- mice. The initial expression of TNF, MIP-2, MCP-1 and ICAM-1 mRNA or protein was equivalent between genotypes at 1h after GalN/LPS administration. However, at subsequent time points, hepatic expression of these genes was decreased in egr-1-/- mice compared to wild type mice. In addition, neutrophil extravasation from hepatic sinusoids into the liver parenchyma was decreased in egr-1-/- mice compared to wild type mice 4h after GalN/LPS. While caspase 3 activation and TUNEL positive nuclei were detected in wild type mice at 4h and 5.5h post GalN/LPS administration, respectively, these markers of apoptosis were delayed in egr-1-/- mice. Delayed development of apoptosis was associated with an extension of survival in egr-1-/- by 1h compared to wild type mice. These data demonstrate that Egr-1 plays an important role in acceleration of hepatic inflammation, apoptosis and subsequent mortality in GalN/LPS-induced acute liver injury.