Seventy-two patients with stage III-IV malignant lymphoma of the poorly differentiated lymphocytic (PDL) type were randomly assigned to initial chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) or to radiotherapy with total body irradiation (TBI). The response and survival rates were similar for CVP and TBI in patients with nodular PDL, with 66% and 67%, respectively, surviving at 7 years. Induction treatment with TBI yielded better response and early survival than CVP for patients with diffuse PDL but a survival advantage did not exist at 5 years, the survival rate being 28% and 25%, respectively. TBI was more easily tolerated than CVP as initial therapy, 19 (51%) of the 37 CVP patients had a complication which required hospitalization during the first six cycles as contrasted to only one of 35 patients receiving TBI who required hospitalization. Most chemotherapy complications were infectious in nature, secondary to relatively severe granulocytopenia, and one patient died from Candida sepsis following the first cycle of CVP. Late complications consisted of two TBI patients who developed a myeloproliferative disorder and two CVP patients who experienced persistent disabling neurotoxic reactions. Durable remissions were not achieved with significant frequency using either form of treatment, indicating a need to evaluate new therapeutic approaches for the management of PDL lymphoma.