Epstein Barr virus (EBV) induced lymphoproliferative disease (EBV-LPD) following organ transplantation is a complex disorder, ranging from polyclonal lymphoproliferations to monoclonal lymphomas. While decreasing or discontinuing immunosuppression has been shown to result in regression of disease in many patients, for those with more aggressive disorders, EBV-LPD can be fatal. Adoptive immunotherapy with EBV specific cytotoxic T cells (CTL) is one potential therapy that has been used successfully in stem cell transplant recipients. We have treated two organ transplant patients with EBV-LPD who had persistent disease despite chemo/radiotherapy with allogeneic EBV CTL. Patient I had a large CNS lymphoma following a renal allograft and received three doses of 5 x l O6 CD3+ EBV CTIV kg from his HLA 4/6 antigen matched father. This patient had detectable increases in levels of EBV specific CTL at intervals following each infusion and is now in remission six months following the last CTL infusion. Patient 2 developed a high grade EBV positive B cell (ymphoma involving multiple lymph nodes and bone marrow six years following liver transplantation. Despite multi-agent chemotherapy and subsequent anti-B cell monoclonal antibodies, the patient continued to have a marrow that was diffusely infiltrated with EBV positive B cells. Following three doses of EBV CTL from his HLA 6/6 matched sibling (same schedule as above), this patient had a > 75% reduction of EBV-LPD cells in the bone marrow, with many cells appearing to undergo apoptosis. This patient continues to be clinically well two months post-infusion. Despite clinical/immunologic responses, donor cells were not detected from peripheral blood in either patient. These findings indicate that allogeneic "third party"EBV CTL can be used successfully for patients with EBV-LPD. The role of this form of therapy for other patient groups with EBV-induced malignancies, and the impact of giving chemotherapy prior to CTL to facilitate (at least temporary) engraftment are being investigated.