Waldenström's macroglobulinemia is a low-grade lymphoplasmacytoid lymphoma characterized by CD20 expression on malignant cells. Several studies have indicated that the anti-CD20 monoclonal antibody rituximab has activity against this disease. Thus, we performed a prospective study in which 17 previously untreated patients with symptomatic macroglobulinemia were treated with rituximab 375 mg/m2 intravenously for 4 weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. Six patients (35%) achieved a partial response after extended treatment with rituximab. Median time to response was 3 months. The median time to progression (TTP) for all patients was 13 months. One of 6 responding patients has progressed at 10 months, while the other 5 patients remain progression free with a follow-up range of > 22-40 months. Eight patients (47%) were rated as stable disease, and their median TTP was 9 months. Treatment with rituximab was well tolerated and was not associated with myelosuppression; one third of the patients experienced infusion-related toxicity, usually fever and chills of mild degree. Our prospective trial of extended rituximab therapy for previously untreated patients with Waldenström's macroglobulinemia indicates that this agent is active, well tolerated, and might be associated with a long period without the need for further treatment. Studies that will combine rituximab with chemotherapy or with other monoclonal antibodies might be of interest.