Abstract: Post-transplant Lymphoproliferative Disorder (PTLD) because of the Epstein–Barr Virus (EBV) is a major concern after pediatric transplantation. The group at greatest risk is EBV-seronegative recipients who receive EBV-seropositive organs. Additional risk factors remain to be determined, including those among EBV-seropositive recipients. In this case-control study, PTLD cases were biopsy-proven over a period of 4 yr (1997–2000, inclusive). Each case was matched with 2 controls, based on the type of organ transplanted and the period of transplantation (±1 yr). Variables compared between cases and controls included those relating to the clinical and virologic profiles and immunosuppressive therapy. Twenty-two cases of PTLD were diagnosed during the study period. PTLD cases occurred at a median of 22.8 months post-transplantation (range 1–131). The median age of cases was 26.2 months (range 6.1–194) compared with 47.4 months (range 0.8–202.2) for controls (p = 0.93). Cases had a higher mean baseline EBV load compared with controls (3.1 log10 (s.d. ± 1.0) vs. 1.6 log10/106 PBMCs (s.d. ± 1.4), with every 1 log increase in viral load resulting in a three times increase in the likelihood of PTLD (p < 0.007). Close to one in four cases of PTLD were EBV-seropositive pretransplantation. These seropositive recipients tended to be older patients with a trend to a worse outcome compared with their seronegative counterparts. The occurrence of PTLD was not associated with the use of any specific immunosuppressants. A significant proportion of PTLD cases occurred among EBV-seropositive transplant recipients, with a tendency towards an unfavorable outcome. Besides EBV-seronegative recipients who receive seropositive organs, some EBV-seropositive pediatric patients are at risk of PTLD. Additional studies are warranted to further define the factors associated with PTLD in EBV-seropositive transplant recipients.