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The role of donor-specific anti-human leukocyte antigen antibodies (DSAs) that develop late after living donor liver transplantation is unknown. Seventy-nine pediatric recipients who had good graft function and underwent protocol liver biopsy more than 5 years after transplantation (median = 11 years, range = 5-20 years) were reviewed. DSAs were determined with the Luminex single-antigen bead assay at the time of the last biopsy, and complement component 4d (C4d) immunostaining was assessed at the times of the last biopsy and the previous biopsy. The donor specificity of antibodies could be identified in 67 patients: DSAs were detected in 32 patients (48%), and they were usually against human leukocyte antigen class II (30 cases) but were rarely against class I (2 cases). These patients had a higher frequency of bridging fibrosis or cirrhosis (28/32 or 88%) than DSA-negative patients (6/35 or 17%, P < 0.001). Fibrosis was likely to be centrilobular-based. DSA-positive patients, in comparison with DSA-negative patients, had higher frequencies of diffuse/focal endothelial C4d staining (P < 0.001) and mild/indeterminate acute rejection [15/32 (47%) versus 5/35 (14%), P = 0.004]. Four DSA-negative patients were off immunosuppression, whereas no patients in the DSA-positive group were (P = 0.048). In conclusion, the high prevalence of graft fibrosis and anti–class II DSAs in late protocol biopsy samples suggests that humoral alloreactivity may contribute to the process of unexplained graft fibrosis late after liver transplantation. Liver Transpl 18:1333–1342, 2012. © 2012 AASLD.