We examined the sex differences in the development of diabetes due to neonatal streptozotocin (STZ) treatment in spontaneously hypertensive rats (SHR) which are more prone to diabetes than normotensive rats. Male and female SHR were intraperitoneally injected with various doses of STZ at 2 days after birth. In those treated with vehicle or 25 mg/kg of STZ, there were no sex differences in plasma glucose levels, which changed little during the 12 weeks of observation. When treated with 50 mg/kg of STZ, however, male SHR developed overt hyperglycemia greater than 300 mg/dl plasma glucose after 8 weeks of age, while females showed a minimal change in plasma glucose levels. When given 75 mg/kg of STZ, female rats developed overt hyperglycemia at 4-6 weeks of age, during which time male SHR showed no apparent hyperglycemia. At 8 weeks or later, however, both males and females had similarly high levels of plasma glucose. Glycosylated hemoglobin at 12 weeks was compatible with plasma glucose levels in each group. The present results indicate that there are sex differences in susceptibility to neonatal STZ treatment and in development of hyperglycemia.