Central perivenulitis (CP) encompasses dropout of zone 3 hepatocytes, red blood cell extravasation, and perivenular mononuclear inflammation. In the liver transplant setting, CP can occur in isolation or it can occur in association with portal-based disease such as acute cellular rejection (PB-ACR). Some CP is also thought to be a manifestation of chronic rejection, particularly when accompanied by zone 3 fibrosis. Prior studies of CP in pediatric liver allografts have been hampered by lack of protocol biopsies and low rates of histologic follow-up. We studied 62 consecutive liver allografts from 55 pediatric patients (age: < or =18 y) who underwent transplant from the years 1995 to 2007. Forty-nine allografts (79%) had > or =1 year of histologic follow-up, 32 (52%) > or =3 years, and 24 (39%) > or =5 years. We reviewed a total of 445 allograft biopsies (mean: 7.2 per allograft) obtained at 2 days to 11 years; 213 (48%) of these were protocol biopsies. Seven explanted livers that were removed during the course of retransplantation for graft failure in this group were also reviewed. All specimens were scored for the following features: (1) CP (mild, moderate, and severe), (2) portal ACR (mild, moderate, and severe), (3) zone 3 fibrosis (mild=perivenular or severe=bridging), and (4) ductopenia. CP was present in 120 (27%) of 445 biopsies, including 73 with CP+PB-ACR, 16 with CP within 1 month of PB-ACR, 27 with isolated CP, 3 with CP+de-novo autoimmune hepatitis, and 1 with CP+Epstein-Barr virus infection. Overall, CP was observed on at least 1 occasion in 41 (66%) allografts. It was not associated with any specific liver function test abnormality or pattern of liver function test abnormalities, it was not associated with vascular compromise as judged by Doppler ultrasound examinations, and it was not related to type of immunosuppression. CP overall was equally prevalent in the early (< or =3 mo) and late (>3 mo) post-transplant periods, but isolated CP increased in the late period. On follow-up, 6 (15%) of 41 allografts with CP developed ductopenic chronic rejection (4 requiring retransplantation) and 10 (25%) developed zone 3-based fibrosis without ductopenia (2 severe, 8 mild). In contrast, none of the 21 allografts without CP developed chronic rejection (P=0.09) and none had zone 3-based fibrosis on their last biopsy (P<0.001). All patients who developed ductopenia had 1 or more episodes of CP+PB-ACR. In contrast, isolated CP [seen in 17 (27%) allografts on at least 1 occasion] was associated with zone 3-based fibrosis in 50%, but did not lead to ductopenic chronic rejection. These results underscore the high frequency of CP in pediatric liver transplantation, occurring in 27% of all allograft biopsies and 66% of allografts overall. CP is most common in conjunction with portal ACR, where it carries a significant risk for the development of zone 3 fibrosis and a trend toward the development of ductopenic chronic rejection.