Posttransplant lymphoproliferative disorder (PTLD) is a frequently fatal complication of organ transplantation, occurring in 2% to 6% of cardiac recipients. Treatment remains poorly defined. Reduction in immunosuppression is effective in a proportion of cases, but mortality on the order of 80% is reported for patients requiring chemotherapy. The reason for such poor outcomes is unclear, but may be partly caused by the concomitant use of immunosuppressives. Nineteen consecutive cardiac recipients with PTLD were studied retrospectively in terms of clinical features and outcome. Patients were managed according to a uniform treatment approach. Initial therapy was a trial of reduced immunosuppression with concomitant acyclovir followed, if unsuccessful, by aggressive combination chemotherapy. The regimen used was predominantly ProMACE-CytaBOM. Six patients with phenotypically polyclonal PTLD presented less than 6 months after transplantation (median 6 weeks). Only 1 of 4 (25%) treated patients responded to reduced immunosuppression; the remainder died of multiorgan failure. Thirteen patients presented with phenotypically monoclonal disease > or = 6 months after transplantation. In 8 of 12 (75%) treated patients initial therapy was reduction in immunosuppression. None achieved complete remission (CR) and 2 experienced fatal rejection. Two patients achieved durable surgical CR. The remaining 8 patients received chemotherapy; 2 of 8 (25%) died during treatment, 6 of 8 (75%) achieved CR. None have relapsed, at a median duration of follow-up of 38 months. Neutropenic sepsis and subclinical doxorubicin cardiotoxicity at a mean cumulative dose of 63 mg/m2 were the principal toxicities. Our data indicate that aggressive chemotherapy is both feasible and effective in phenotypically monoclonal PTLD refractory to reduced immunosuppression. ProMACE-CytaBOM is well suited to cardiac recipients, minimizing doxorubicin exposure and obviating the need for concurrent immunosuppressives.