Autoimmune hepatitis (AIH) is usually a chronic portal-based hepatitis with prominent plasma cells. Although necroinflammatory activity throughout the lobule is described, centrilobular necrosis (CN) is only rarely the predominant pattern of injury. Recognition of the possibility of AIH in zone 3 hepatitis will lead to prompt steroid therapy and may avert cirrhosis. We report the clinicopathologic features of 6 cases of AIH with CN. The 3 females and 3 males averaged 48 years of age (range 32-66 years). Four patients had a history of autoimmune disorders. All had elevated transaminases and negative serology for viral hepatitis B and C. One had a history of ethanol use. One patient was taking interferon-beta and 1 patient was taking atorvastatin, but none of the patients was taking medication with a temporal relationship to suggest a drug hypersensitivity hepatitis. All patients had positive antinuclear antibody, anti-smooth muscle antibody, or both, although 1 patient was negative for autoantibodies at initial laboratory testing. Four biopsies showed confluent zone 3 necrosis, whereas two biopsies showed spotty CN. Portal inflammation was relatively mild in all cases. Plasma cells were few to numerous in both zone 3 and portal tracts in four biopsies; they were absent in 2 cases. All patients responded to steroid therapy. Two patients relapsed, and rebiopsy in 1 of them showed CN, bridging necrosis, and an increase in the degree of portal-based hepatitis. Another patient was not treated initially; a second biopsy 35 months after presenting revealed periportal hepatitis as well as CN. The histologic spectrum of AIH should be expanded to include zone 3 hepatitis. As with classic AIH, most patients with CN demonstrate serologic and clinical evidence of autoimmunity. Subsequent biopsies in patients with a centrilobular pattern may show evolution to portal-based hepatitis characteristic of AIH but may also show persistence of the zone 3 hepatitis. Unlike other causes of zone 3 hepatitis, AIH is steroid responsive; therefore, timely diagnosis is important.