The histologic diagnosis of acute hepatic allograft rejection is usually based upon the identification of characteristic portal tract features. In addition to these l centrilobular alterations such as central vein endothelialitis, zone 3 inflammation, and hepatocyte necrosis may also he seen during episodes of acute rejection. The purpose of this study was to identify any differences in the subsequent clinical course of patients with and, without centrilobular alterations during their firs! biopsy-proven episode of acute rejection. Acute rejection, was diagnosed at least once in 35 River recipients who had undergone allograft biopsy. Of these, 15 (43%) had centrilobular alterations in their first posttransplant biopsy. These 15 patients developed ductopenia (60% vs. 30%) and subsequent episodes of acute rejection. (53% vs. 25%) more often than did the 20 patients who lacked centrilobular alterations in their first posttransplant biopsy. Time to first episode of acute rejection and rates of subsequent recurrent hepatitis and death were similar between the 2 groups. Patients with contrilobular alterations during a first episode of acute rejection are more likely to have subsequent episodes of acute rejection and to develop features of chronic rejection than are patients without these changes. These patients may benefit from more vigilant clinical follow-up and/or higher levels of immunosuppression.