T-cell suppression prevents acute cellular rejection but causes life-threatening infections and malignancies. Previously, liver transplant (LTx) rejection in children was associated with the SNP rs9296068 upstream of the HLA-DOA gene. HLA-DOA inhibits B-cell presentation of antigen, a potentially novel anti-rejection drug target. Using archived samples from 122 Caucasian pediatric LTx (including 77 described previously), we now confirm the association between rs9296068 and LTx rejection (p=0.001, OR=2.55). Next-generation sequencing reveals that the putative transcription-factor-(CTCF)-binding SNP locus rs2395304, in linkage disequilibrium with rs9296068 (D’=0.578, r2=0.4), also associates with LTx rejection (p=0.008, OR=2.34). Further, LTx rejection is associated with enhanced B-cell presentation of donor antigen relative to HLA-non-identical antigen in a novel cell-based assay, and with a downregulated HLA-DOA gene in a subset of these children. In lymphoblastoid B-(Raji) cells, rs2395304 co-immunoprecipitates with CTCF, and CTCF knockdown with morpholino antisense oligonucleotides enhances alloantigen presentation and downregulates the HLA-DOA gene, reproducing observations made with HLA-DOA knockdown and clinical rejection. Alloantigen presentation is suppressed by inhibitors of methylation and histone deacetylation, reproducing observations made during resolution of rejection. Enhanced donor antigen presentation by B-cells and its epigenetic dysregulation via the HLA-DOA gene represent novel opportunities for surveillance and treatment of transplant rejection.