Centrilobular necrosis (CLN) in liver allografts can be a difficult lesion to interpret histologically. Although well recognized in association with developing chronic rejection, recent studies have described the lesion in other disease processes. To clarify the histological features allowing a specific diagnosis to be made, biopsies from 54 patients with CLN occurring more than 15 days after transplantation were assessed. They were classified, based on histology and clinical outcome, as CLN with acute cellular rejection (ACR)(n=17), CLN with hepatitis (n=15), CLN with developing chronic rejection (CR)(n=12), and CLN of other etiologies (n=10). Discriminating features (p<0.05) were: CLN and ACR showed bile duct injury, endothelialitis and acinar congestion. CLN and CR showed severe bile duct injury, bile duct loss or centrilobular swelling. CLN and hepatitis was usually a diagnosis of exclusion, although interface hepatitis was more frequent in this group. Two types of hepatitis were seen. Transient, self-limited hepatitis (n=7) resolved spontaneously and may overlap with cases of ACR. Chronic hepatitis with CLN (n=8) often was seen in patients transplanted for autoimmune hepatitis (AIH) or fulminant seronegative hepatitis. Cases of AIH usually demonstrated plasma cell predominance in the portal and acinar inflammatory infiltrates. Importantly, there was considerable overlap in the individual histological features between the groups accounting for the diagnostic difficulty, and accurate diagnosis relies on the presence of a constellation of features. Patients with CR or vascular complications generally required retransplantation or died, but in the groups with ACR or hepatitis the outcome was more favorable. In the majority of liver allograft biopsies showing CLN, it is possible to make a specific diagnosis allowing specific therapy to be instituted, thus improving graft survival.