Fourteen consecutively referred, symptomatic patients with Waldenstrom's macroglobulinemia (ages 52–87 yr) have been treated with the 5-drug M-2 protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone). Three patients were previously treated and 11 patients were untreated. The majority of patients were symptomatic from hyperviscosity. All patients have responded to therapy. Two patients have achieved complete remissions and 12 patients partial remissions to date. None of the patients with symptomatic hyperviscosity has required plasmapheresis since therapy with the M-2 has been initiated. Lymphadenopathy, hepatosplenomegaly, and anemia have also responded to treatment. Follow-up data are limited, with survival from initiation of therapy with the M-2 ranging from 2+ to 35% mo (median 17+ mo) 2+-40+ mo from time of diagnosis). Combination chemotherapy for Waldenstrom's macroglobulinemia with the M-2 protocol appears to increase the response rate in patients with symptomatic disease. Further survival analysis will be carried out.