The effect of thymectomy performed at weaning (3 weeks) and at 6-7 weeks of age on the incidence of diabetes was examined in the non-Obese diabetic (NOD) mouse, a spontaneous model of immunologically mediated insulin-dependent diabetes similar to human type I diabetes. When performed at weaning, thymectomy led to a dramatic increase in the incidence of diabetes in NOD females in comparison to sham-thymectomized animals. Conversely, no change in the incidence of the disease or the expression of insulitis was noted when thymectomy was performed in NOD males. When delayed beyond 6-7 weeks of age, thymectomy had no effect on NOD males and females. Flow cytometry analysis of spleen cells from intact mice and mice thymectomized at weaning or at 6-7 weeks of age demonstrated a significant depletion of the T cell subsets in both groups of thymectomized animals. These results indicate that the onset of diabetes in NOD mice is submitted to thymic regulation and that the T cell depletion induced by thymectomy at weaning accelerates the disease, an effect possibly due to the loss of some T cell-dependent suppressor mechanisms.