Hypothesis: Since studies have found the liver enzyme α-glutathione S- transferase (αGST) to be a marker of hepatic injury after hemorrhagic shock, αGST also may serve as a sensitive indicator of hepatocellular damage during the early stage of polymicrobial sepsis. Design, Interventions, and Main Outcome Measures: Male adult rats were subjected to the cecal ligation and puncture (CLP) model of polymicrobial sepsis or sham operation, followed by fluid resuscitation with isotonic sodium chloride solution. Systemic blood samples were taken at 2, 5, 10, or 20 hours after CLP or sham operation. Plasma levels of αGST and lactate were determined using an enzyme immunoassay and enzymatic assay, respectively. Additional animals were examined for morphologic alterations in liver ultrastructure of septic animals using electron microscopy. Results: A similar level of αGST (mean ± SEM, 30.5 ± 3.5 μg/L) was found in the sham group at all measured time points. Although plasma levels of αGST did not change at 2 hours after CLP, they were elevated by 249% at 5 hours after the onset of sepsis and continued to increase throughout the septic course. Plasma lactate levels were significantly increased only at 20 hours after CLP (P<.001). Previous studies have shown that liver transaminase levels did not increase at 5 hours, but at 10 and 20 hours after CLP. In addition, electron microscopy revealed structural changes in hepatocyte morphology at 5 and 20 hours after CLP that were indicative of hepatocellular injury. Conclusion: Since plasma αGST levels increased earlier than plasma lactate and liver transaminase levels, αGST may be a more sensitive indicator of early liver injury and should be used in monitoring hepatocellular damage during the progression of sepsis.