Since the adoption of rituximab, the importance of doxorubicin and vincristine as treatment components remains to be clarified in Waldenström's macroglobulinemia (WM). We therefore examined the outcomes of symptomatic patients with WM who received CHOP-R (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab; n = 23), CVP-R (cyclophosphamide/vincristine/ prednisone plus rituximab; n = 16), or CP-R (cyclophosphamide/prednisone plus rituximab; n = 19) at our institution. Baseline characteristics for all 3 cohorts were similar for age, previous therapies, bone marrow involvement, hematocrit, platelet count, and serum beta2-microglobulin, though serum immunoglobulin M levels were higher in patients treated with CHOP-R (P < or= .015). The overall response rates (ORR) and complete response (CR) rates to therapy were as follows: CHOP-R (ORR, 96%; CR, 17%); CVP-R (ORR 88%; CR 12%); CP-R (ORR, 95%; CR, 0%); P = not significant. Adverse events attributed to therapy showed a higher incidence for neutropenic fever and treatment-related neuropathy for CHOP-R and CVP-R versus CPR (P < .03). The results of this study demonstrate comparable responses among patients with WM receiving CHOP-R, CVP-R, or CP-R, though a significantly higher incidence of treatment-related neuropathy and febrile neutropenia was observed among patients treated with CVP-R and CHOP-R versus CP-R. The use of CP-R might provide analogous treatment responses to more intense cyclophosphamide-based regimens while minimizing treatment-related complications in patients with WM.