The Pediatric Oncology Group (POG) adopted a histology-based approach to the management of pediatric non-Hodgkin's lymphomas (NHL) utilizing the National Cancer Institute Working Formulation for Clinical Usage. Patients with diffuse large cell lymphoma (DLCL) were treated on a separate protocol from small cell diffuse undifferentiated or lymphoblastic lymphomas. This study assessed the overall and event free survival of children with DLCL and determined the effects of cyclophosphamide upon these end-points in a prospective randomized trial. One hundred and twenty eligible stage III or IV NHL patients with the confirmed diagnosis of diffuse large cell or immunoblastic histology were enrolled on study between October 1986 and November 1991. Patients were randomized to receive or not receive cyclophosphamide; 58 received cyclophosphamide, doxorubicin, vincristine, 6-mercaptopurine (6-MP), and prednisone (ACOP+) and 62 were treated with doxorubicin, vincristine, 6-MP, and prednisone (APO). In both treatment programs methotrexate was substituted when the doxorubicin cumulative dose reached 450 mg/m2. Radiation was administered to bulky disease if progression or no response were observed after induction therapy. Planned duration of therapy was 12 months.The 5-year event free survival (EFS) rates of patients treated with ACOP+ versus APO were 62% ± 7% and 72% ± 6%, respectively. While there was no statistically significant difference between the two treatment arms (p=0.28), we can only say that we are 95% confident that the difference in 5-year EFS falls in the wide range from 28% in favor of APO to 8% favoring ACOP+. Marrow suppression was the main toxicity with one fatal infection. There were three other deaths on study due to respiratory failure in patients with mediastinal masses. Only one patient experienced cardiotoxicity requiring discontinuation of doxorubicin. Ten patients received radiation therapy to achieveIn conclusion the efficacy of elimination of cyclophosphamide from the treatment program of children and adolescents with advanced stage diffuse large cell lymphoma was inconclusive as to its effect on EFS. Furthermore, the majority of the patients (92%) did not require any radiation therapy to bulky disease indicating that the chemotherapy regimens are quite efficient for achievement of complete remission.