Translocation of microorganisms and endotoxin (LPS) across the gastrointestinal mucosa may exacerbate the inflammatory response and potentiate hepatic injury associated with hemorrhagic shock. Lipopolysaccharide binding protein (LBP) augments LPS signaling through TLR4. In addition, evidence suggests that TLR4-mediated injury in liver ischemia/reperfusion occurs through the IRF-3/MyD88 independent pathway. We hypothesized that administration of LBP inhibiting peptide, LBPK95A, given at the time of resuscitation would reduce liver inflammation and injury in a murine model of hemorrhagic shock by limiting LPS-induced activation of the MyD88 independent pathway. Hemorrhagic shock was induced in male, C57BL/6 mice; a mean arterial blood pressure of 35 mmHg was maintained for 2.5 h. LBPK95A peptide or equal volume Lactated Ringer's solution was administered followed by fluid resuscitation. Mice were sacrificed at 2 and 6 h post-resuscitation. At 2 h, liver mRNA levels revealed a significant reduction in IFN-β, a cytokine produced via the MyD88 independent pathway, with LBPK95A treatment. However, mRNA levels of TNF-α, a cytokine associated with the MyD88 dependent pathway, were unaffected by treatment. The LBP inhibitory peptide did selectively reduce activation of TLR4 signaling via the IRF-3/MyD88 independent pathway. These results suggest that LBP promotes cytokine production through the MyD88 independent pathway during hemorrhagic shock.