Background.The treatment of posttransplant lymphoproliferative disorder (PTLD) remains empirical. We review our treatment of seven cases of PTLD consisting of five interventions: 1) reduction of immunosuppression; 2) antiviral drugs; 3) interferon-&agr;; 4) gamma-globulins; and 5) anti-CD19 monoclonal antibodies.Methods and Results.Seven consecutive patients who had undergone a simultaneous pancreas-kidney, liver, heart, or kidney transplantation were treated. One patient acquired a primary EBV infection with an oligoclonal immunoblastic lymphoma early after pancreas-kidney transplantation; all others developed a monoclonal polymorphic or immunoblastic lymphoma 2 to 123 months after transplantation. In all patients extranodal sites were involved, in three the graft was also involved. Five patients received the full quintuple approach and all rapidly obtained a complete remission (CR) with a median follow-up of 31 months (7-74 months). Of the two patients who did not receive interferon-&agr; for fear of graft rejection one responded slowly with a CR after 7 months, and the other obtained a rapid CR followed by a relapse at 4 months. All three patients with a liver or heart transplant could keep their graft. All patients are still alive with a median follow-up of 31 months (7-74 months).Conclusion.This combined approach resulted in a favorable outcome in patients with high risk monoclonal PTLD after solid organ transplantation.