Posttransplantation lymphoproliferative disorder (PTLD) is a life-threatening Epstein-Barr virus (EBV)-associated B-cell malignancy occurring in 1% to 2% of renal transplantation patients. Host- and PTLD-related factors determining the likelihood of tumor response following reduction of immune suppression (IS) and antiviral therapy remain largely unknown. Standard therapy for PTLD is not well established. Eleven consecutive renal transplantation patients who developed EBV-positive PTLD 8 to 94 months after allografting were uniformly treated with acyclovir and IS reduction. All PTLDs were EBV-positive diffuse large B-cell lymphomas. Ten patients (91%) obtained a durable complete response (CR), and 9 (82%) have remained in continuous CR with a median follow-up of 29 months. Five patients (45%) lost their allograft. Of these, 4 patients had PTLD affecting the transplanted kidney. Peripheral blood CD8(+) T cells increased significantly (P =.0078) from baseline in 8 responders available for analysis. One of 2 patients whose absolute CD8(+) T-cell count subsequently dropped to baseline after IS reduction relapsed. The expanded CD8(+) T cells from 2 responders specifically recognized an immunodominant peptide from the EBV lytic gene BZLF-1. Another lytic EBV gene, thymidine kinase, was expressed in all 8 PTLDs tested. IS reduction and antiviral therapy for PTLD after renal transplantation is a highly successful therapeutic combination, but the risk of graft rejection is significant, particularly in patients with PTLD involving the renal allograft. A sustained expansion of CD8(+) T cells and a cellular immune response to EBV lytic antigens may be important for PTLD clearance in renal transplantation patients.