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During the first episode of acute cellular rejection (ACR) after liver transplantation, centrilobular changes in liver biopsy specimens may be possible indicators of subsequent episodes of ACR, early chronic rejection, or acute graft loss. The purpose of this study was to identify differences between the histopathological findings in liver biopsy specimens obtained during the first rejection episode in patients who subsequently developed further episodes of ACR and those who did not. The histopathological findings in 22 patients who had a single episode of acute rejection (group 1) were compared with those in 23 patients who had multiple episodes of acute rejection (group 2). Only the first liver biopsy samples of the latter group were taken into consideration. We assessed the predictive value of centrilobular necrosis, central vein endothelialitis, pericentral inflammation, hepatocellular ballooning, cholestasis, hepatocellular apoptosis, lobular inflammation, the degree of portal eosinophilia, and characteristic portal tract features in poor responders to antirejection treatment. The time to the first episode of ACR and the rejection activity index were similar in patients in both groups. Hepatocellular apoptosis, hepatocellular ballooning, and central vein endothelialitis were common features of both groups. The incidences of pericentral inflammation, centrilobular necrosis, and portal eosinophilia were significantly higher in patients in group 2 than in those in group 1 (P < 0.05). Patients with pericentral inflammation, centrilobular necrosis, and marked portal eosinophilia during an initial episode of acute rejection may be more likely to develop subsequent episodes of ACR. Liver Transpl 14:214–219, 2008. © 2008 AASLD.