Radioimmunotherapy targeting CD20 is a promising novel treatment for lymphoma. Prior trials have established the safe dose of Zevalin ((90)Y-ibritumomab tiuxetan; IDEC Pharmaceuticals) for patients with no more than 25% bone marrow (BM) involvement. Zevalin is expected to be an effective treatment for WM; however, the safe dose has not been defined. A phase I clinical trial has been designed to define the maximum-tolerated dose (MTD) of Zevalin in patients with WM and BM involvement up to 50%. Eligible patients need to have adequate hematologic indices (absolute neutrophil count [ANC] > 1,500/microL, platelets > 100,000/microL). The starting dose of (90)Y-Zevalin is 0.08 mCi/kg. Dose escalation by 0.04 mCi/kg in cohorts of three to six patients will be performed. Patients will be re-treated at 12 weeks if there is no complete response, no progression, and no dose-limiting toxicity. If the degree of BM involvement remains in the 20% to 50% range, re-treatment will involve a similar dose of Zevalin; if it is <20%, patients will receive Zevalin to the maximum allowed cumulative dose of 0.4 mCi/kg (or 0.3 mCi/kg for mild thrombocytopenia). Despite the phase I design, the re-treatment provision is expected to result in significant clinical benefit.