Oral administration of autoantigens to adult mice is an effective means of suppressing experimental autoimmune diseases including diabetes and experimental allergic encephalomyelitis (EAE). Different mechanisms are involved in induction of oral tolerance including active suppression, anergy and deletion. Oral tolerance is generally not inducible in the neonatal period and we previously found that EAE development in Lewis rats is enhanced when animals are fed myelin antigens as neonates. Here we report the unexpected finding that oral administration of either human insulin or the insulin B-chain peptide (10-24) in the neonatal period suppresses the development of diabetes in the non-obese diabetic (NOD) mouse. Furthermore, suppression of diabetes by neonatal oral human insulin was more effective than oral human insulin given to NOD mice (3-4 weeks of age). No protection against EAE was observed in NOD mice neonatally fed PLP (48-70) or MOG (35-55) peptide prior to EAE induction, whereas adult NOD mice orally tolerized to these peptides were protected against EAE. Neonatal administration of insulin B-chain peptide also suppressed cyclophosphamide induced diabetes in the NOD whereas oral insulin administration to 4-week-old NOD mice had no effect, suggesting that the mechanism of disease suppression in the neonate involved anergy or deletion. Our findings that neonatal feeding of human insulin or insulin B-chain peptide is effective in inhibiting diabetes when given to the NOD mouse may have applications in preventing diabetes in high risk human populations.