The autoimmune diabetic syndrome of the biobreeding (BB) rat currently constitutes the best animal model for human type I diabetes. Since prediction of human beings at high risk for development of diabetes by immunologic and physiologic parameters is not possible at present, we investigated the feasibility of immunoprediction of diabetes in normoglycemic BB diabetes-prone (BBdp) rats. Peripheral blood lymphocyte counts (PBLC) accurately predicted future development of diabetes in a cohort of 50 BBdp rats (100% specificity, 95.8% sensitivity for PBLC less than 3800/mm3). We also assessed the fate of normal islets transplanted from MHC-compatible non-diabetes-prone Wistar Furth (WF) donors in the prediabetic milieu of BBdp hosts that were known on the basis of their PBLC destined either to become diabetic or to remain normoglycemic. In 13 BBdp rats in which diabetes was predicted the native pancreatic beta cells were eliminated at 35 days of age with streptozocin and replaced with transplanted WF islets. Neonatally induced tolerance of WF antigens prevented rejection. After successful islet transplantation, spontaneous diabetes occurred in 100% (5/5) of the rats in which the development of diabetes was predicted. The identical protocol in eight rats predicted not to have diabetes resulted in permanent normoglycemia in all. We conclude that normal islets are susceptible to anti-islet autoimmunity after transplantation in the prediabetic period.