Introduction: The three main choices for the primary treatment of WM are alkylating agents, nucleoside analogues and rituximab. There is evidence that combinations of nucleoside analogues and rituximab are highly active. However, when such regimens are applied, there are concerns regarding myelosuppression, immunosuppression and impact on stem cell collection. We designed a phase II study which included previously untreated WM patients (with clearly defined criteria for initiation of treatment) who were treated with a combination of dexamethasone, rituximab and cyclophosphamide. Patients and methods: Patients with WM received primary treatment with dexamethasone 20 mg i.v. followed by rituximab 375mg/m2 i.v. on day 1 and cyclophosphamide 100mg/m2 p.o. bid days 1–5 (total dose 1000 mg/m2). This regimen was repeated every 21 days for 6 courses. Results: Since July 2002, 34 patients have been enrolled in this multicenter study. Patients characteristics include: median age of 75 years (range 53 to 86 years), 59% male, 25% B symptoms, 25% splenomegaly, 35% lymphadenopathy, 25%hyperviscosity syndrome, 59% hemoglobin 4 mg/dl. So far, on an intent-to-treat basis, 78% of patients achieved at least 50% reduction of serum monoclonal protein concentration. The median time to response was 3.6 months (range 0.7 months to 5.4 months). With a mean follow-up of 18 months, 90% of patients are progression-free. With the exception of one patient who died of interstitial pneumonia, the DRC regimen was well tolerated. 15% of patients developed grade 3, 4 neutropenia. Mild or moderate effects related to rituximab infusion such as fever, rigors and headache were seen in 20% of patients. Conclusions: We administered a regimen which combined rituximab with cyclophosphamide, a non-stem cell toxic alkylating agent. The DRC regimen is an active and well tolerated primary treatment for symptomatic patients with WM. Patient accrual and evaluation is ongoing.