We treated 2-week-old and 8-week-old non-obese diabetic (NOD) mice with 1 mg of anti-L3T4 MoAb weekly for 4 weeks. This short-term treatment of anti-L3T4 MoAb prevented the development of overt diabetes in NOD mice, in both groups, even after cessation of the therapy. However, there were overt mononuclear cell infiltrations in the majority of islets, and no appreciable differences in the degree of insulitis between treated and control mice. There were also no significant differences in the percentage of L3T4+ T cells expressing V beta 5, V beta 8 and V beta 11 antigens between the treated and the control group. In contrast, most of the male NOD mice injected with 200 mg/kg of cyclophosphamide did not become diabetic when the spleen cells from the MoAb-treated female NOD mice were transferred to these animals 48 h before the cyclophosphamide injection. Thus, the tolerance induced by the short-term administration of anti-L3T4 MoAb to NOD mice may not be due to clonal deletion, but rather to newly generated suppressor cells in the animals.