Patients with advanced indolent lymphoma often have long survival (median, 4 to 8 years) in spite of frequent relapses. The inability of combination chemotherapy or radiation therapy (RT) to render patients disease free has led to radically divergent treatment approaches. Initial treatment may vary from aggressive combined modality therapy to no initial treatment. We sought to evaluate these two divergent approaches in a randomized trial of advanced indolent lymphomas (nodular, poorly differentiated lymphocytic; nodular mixed; diffuse, well-differentiated lymphocytic; diffuse, intermediately differentiated lymphocytic; and diffuse, poorly differentiated lymphocytic). A total of 104 patients were entered: 44 were randomly assigned to "watch and wait" in which only carefully defined, limited RT was administered if necessary; 45 were randomly assigned to aggressive combined modality treatment with prednisone, methotrexate, doxorubicin, cyclophosphamide, plus etoposide plus mechlorethamine, vincristine, procarbazine, prednisone (ProMACE-MOPP), followed by total nodal irradiation (TNI); and 15, with symptoms requiring initial therapy, received the identical combined treatment but were not randomly assigned. Of 41 evaluable patients on watch and wait, 23 (56%) have still not required systemic therapy, although 16 (39%) have received limited RT. Median time to crossover was 34 months. Of 18 patients crossed over, seven of the 16 who completed therapy (43%) achieved CR; two (11%) have relapsed. Histologic progression was seen in six (15%) of 41 patients on watch and wait without intervening chemotherapy. Of 45 patients randomly assigned to chemotherapy, 37 (82%) have completed induction therapy, and 29 of the 37 (78%) achieved CR. Twenty-five of those 29 patients (86%) are still in their first remission. Median duration of initial remission has not been reached but will exceed 4 years.