The incidence of diabetes in NOD mice is reduced following a single neonatal injection of the anti-CD3 antibody, 145.2C11. We now show that the reduction in incidence is greater when the antibody is given in the first than in the third week of life. Anti-CD3 antibody injected in macro-aggregated form did not protect the recipients from insulitis and protection was diminished when elimination of the antibody was accelerated by injecting anti-hamster IgG. Protection was not reversed when anti-CD3 injection was followed by anti-CD4 and anti-CD8. Animals neonatally injected with anti-CD3 were not protected from the induction of diabetes following transfer of spleen cells from diabetic donors. These results contrast with the view that anti-CD3-mediated protection from diabetes depends on a long-lived change in recipient T cells. The findings are consistent with immunosuppression alone being an adequate explanation for the effect of anti-CD3 antibody on susceptibility to diabetes in NOD mice.