Patients with recurrent or refractory Hodgkin's and non-Hodgkin's lymphoma are increasingly being treated with high-dose therapy and hematopoietic cell transplantation. As minimal disease status at the time of transplant has been a repeatedly proven significant prognostic factor for long-term survival, effective initial cytoreduction is an important step in the process. Modern chemotherapy programs for Hodgkin's lymphoma include virtually all active agents and little is left for effective salvage. Mitoxantrone is an active agent in lymphoma that is not generally used in first-line treatment. The aim of this study was to determine toxicity and response rate to CN3OP (fractionated mitoxantrone 6 mg/m2 on days 1, 2, and 3, combined with standard dose cyclophosphamide, vincristine, and prednisone) in 44 patients with relapsed or refractory lymphoma. Most of patients had advanced disease and one or more extranodal sites at relapse. Median response duration to immediate past therapy was four months, and one third of patients had not responded to prior treatment. A median of 4 cycles of CN3OP were given per patient for a total of 173 cycles. Grade III-IV neutropenia occured in 53% of cycles, Grade I-III mucositis in 24%, and Grade I-III infection in 17% of cycles. Of 34 evaluable patients with Hodgkin's lymphoma 12 (35%) achieved complete remission (CR) and 15 (44%) partial remission (PR) for an overall response rate of 79%. Two of five evaluable non-Hodgkin's lymphoma patients responded with PR. Median overall survival and event free survival in the entire group was 29 months and 11 months respectively. At this time 16 patients have died; 12 of lymphoma, two of unknown cause and two of other causes. Complete response to CN3OP correlated with survival. CN3OP is an effective and safe regimen for cytoreduction in Hodgkin's lymphoma patients pretreated with doxorubicin/alkylator/etoposide-containing primary therapies.