We investigated whether the development of spontaneous T-cell-mediated type I diabetes in NOD mice is influenced by B cells and immunoglobulin (Ig). During the first 4 weeks of life, B-cell development was suppressed by repeated administration of rabbit anti-mouse IgM (RaIgM), while controls received polyclonal rabbit Ig (NRIg). A reduction in the incidence of diabetes, as well as in development of insulitis, was observed after either of these treatments. However, the effect on insulitis was more pronounced in mice treated with RaIgM compared with those treated with NRIg. Furthermore, while the optimal effect of NRIg was obtained after a single injection at birth, the additional effect of RaIgM on development of insulitis was observed only after continued treatment for the first 4 weeks of life. Taken together these data suggest a possible role of Ig/B cells in the development of autoimmunity in the NOD mouse. The additional effect observed after continued suppression of the neonatal B-cell development suggests that this population may contribute significantly to the establishment of an auto-aggressive lymphocyte repertoire in the NOD mouse.