Post-transplantation lymphoproliferative disease (PTLD) is a complication of organ transplantation with high mortality. Predicting response to first line therapy, reduction of immune suppression (RISM), is difficult because of the heterogeneity of lesions and disease behavior. We sought to determine if BCL6 protein expression in PTLD cells is associated with poor outcome. In a cohort of 25 children with PTLD, 9 of the patients’ tumor specimens were positive for BCL6 protein expression. Eight of 13 monomorphic lesions were BCL6 positive, compared to 1 of 11 evaluable polymorphic lesions (p=0.01). Only 1 of the patients with BCL6 expression responded to reduced immune suppression (p=0.19). Recipients of heart transplants who developed PTLD had reduced overall survival rates compared to recipients of other organ transplants that developed PTLD (p=0.04).