Radioimmunotherapy capitalizes on the radiosensitivity of non-Hodgkin lymphoma (NHL) and the targeted nature of monoclonal antibodies. In an attempt to reverse bone marrow infiltration with B-cells and optimize the biodistribution of Yttrium-90 (90Y)-ibritumomab tiuxetan, we conducted a phase I study combining a single course of 90Y- ibritumomab tiuxetan after a 4-weekly course of rituximab in relapsed or refractory low-grade or transformed CD20+ B-cell NHLs with <25% marrow involvement. The 0.4 mCi/kg dose was associated with 80% grade-4 cytopenias. Dose escalation was held, and 6 patients were enrolled at a 0.3 mCi/kg cohort. As the 0.3 mCi/kg dose was well tolerated, the 0.4 mCi/kg cohort was expanded to 6 additional patients. In the expansion cohort, grade-4 cytopenia developed in 33%. Further dose escalation was held, and the maximum tolerated dose was determined at 0.4 mCi/kg. With this regimen, marrow involvement decreased in all patients with complete clearance in 50%. The overall response rate was 82%. With a median follow-up of 31.7 months, the median progression-free survival and time to next treatment were 12.3 and 10.9 months, respectively. Although this regimen was associated with a high response rate, the hematologic toxicity was higher than with the standard 90Y-ibritumomab tiuxetan regimen. © Copyright 2013, Mary Ann Liebert, Inc. 2013.