Yttrium-90 is a potent θ-emitting radionuclide with potential for therapy of lymphoma. A monoclonal antibody against Lyl, the murine homologue of human CD5, was labeled with 90Y and found to selectively bind to Lyl-positive, radiation-sensitive, EL4 mouse lymphoma cells. When tested in this aggressive model of T cell lymphoma, in vivo studies in C57BL/6 mice showed that a single 140-μCi i.p. dose of 90Y-anti-Lyl, given 1 day after i.v. injection of a lethal dose of EL4 cells, resulted in significant but transient improvement in survival. Protection was selective, since a 90Y-labeled irrelevant control antibody did not prolong survival. Biodistribution studies showed that protection was likely limited by inadequate localization of labeled antibody to tumor. Importantly, labeled anti-Lyl specifically localized in the immunological tissue (spleen and thymus) and lowered the WBC count, perhaps limiting the tolerated dose. Myelosuppression, which is considered one of the major side effects associated with 90Y usage, was not a lethal complication, since WBC counts recovered in mice given a 140-μCi dose of 90Y-anti-Lyl without EL4 cells and 100% of these animals survived. The maximum tolerated dose was less than 200 μCi. Despite the high localization of 90Y-anti-Lyl in spleen, splenectomies of tumor-injected mice did not improve the antitumor efficacy of radiolabeled antibody. Further evidence for inadequate delivery of radionuclide to tumor was shown when external total-body irradiation was given to mice given injections of a lethal dose of EL4 tumor cells. Comparison of internal and external irradiation studies indicated that the partially protective effect of 140 μCi 90Y-anti-Lyl was equivalent to external radiation of only 100–200 cGy. Because this model reflects the current clinical limitations of radiolabeled antibodies for therapy, including partial antitumor efficacy, delivery of labeled anti-T cell antibodies to the immune system, and low maximum tolerated dose, the model may be useful for examining strategies which could increase the tolerated dose and therapeutic efficacy. © 1991, American Association for Cancer Research. All rights reserved.