Hypothesis: Recent studies have shown that intracellular signaling pathways, such as the mitogen-activated protein kinases, play a pivotal role in the activation of the inflammatory response. We hypothesized that administration of a specific mitogen-activated protein kinase inhibitor, PD 98059, at the end of resuscitation following severe hemorrhagic shock can reduce the plasma levels of interleukin 6 (IL-6) and hepatocellular damage. Design: Prospective controlled animal study. Settings: Medical school-affiliated university hospital. Interventions. Male Sprague-Dawley (275-325 g) rats underwent laparotomy (ie, soft tissue trauma) and were then bled to a mean arterial pressure of 40 mm Hg for approximately 90 minutes. The animals were then resuscitated with 4 times the bleed-out volume using Ringer lactate solution for 60 minutes. PD 98059, an inhibitor of extracellular signal-regulated kinases (ERKs) 1 and 2 (750 mmol/L), or vehicle (dimethyl sulfoxide and isotonic sodium chloride solution) was administered intravenously as a bolus at the end of resuscitation. Main Outcome Measures: At 24 hours after resuscitation or sham operation, plasma levels of IL-6 and α-glutathione S-transferase were determined with enzyme-linked immunosorbent assay and enzyme immunoassay, respectively. Moreover liver sections were stained with monoclonal antibody against the phosphorylated form of ERKs. Results: At 24 hours following trauma hemorrhage and resuscitation, plasma levels of IL-6 and α-glutathione S-transferase were markedly elevated. Administration of PD 98059, however, reduced levels to sham values. Moreover, liver expression of phosphorylated ERKs was found in the cytosol and nuclear compartment of hepatocytes only following trauma hemorrhage. Conclusion: Administration of PD 98059 (ie, inhibition of intracellular signaling pathways) may represent a feasible approach to blunt the inflammatory response and improve outcome following traumatic injuries and hemorrhagic shock.