<b><i>Background:</i></b> Not all patients with diffuse large B-cell lymphoma (DLBCL) are candidates for aggressive regimens. ⁹⁰Y ibritumomab tiuxetan (⁹⁰Y-IT), an anti-CD20 radionuclide-conjugated antibody, has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile. <b><i>Methods:</i></b> This phase II trial investigated the overall response rate (ORR), event-free survival (EFS), overall survival (OS) and toxicity of treatment with ⁹⁰Y-IT (0.4 or 0.3 mCi ⁹⁰Y/kg based on platelets) followed by rituximab maintenance therapy in patients with DLBCL not candidates for transplant. <b><i>Results:</i></b> 25 patients were enrolled. At best response 8 patients obtained a complete response (CR) and 1 a partial response (ORR 36%). Median EFS was 2.5 months and OS 8.1 months. No patient who obtained CR later relapsed systemically. Two patients were free of disease at the 61- and 100-month follow-ups; 65% had grade 3/4 thrombocytopenia, but no significant bleeding was observed. Grade 3 nonhematologic toxicity occurred in 36%. Patients who had progressed through a rituximab-containing regimen responded poorly. <b><i>Conclusion:</i></b> The ORR of 36% with ⁹⁰Y-IT as salvage therapy for DLBCL while inferior to more aggressive regimens is significant with acceptable toxicity. For a subset of patients not candidates for salvage with autologous transplant, this treatment strategy can produce a durable, long-lasting remission.