Whether the increased capillary permeability characteristic of diabetes extends to the blood-brain barrier is presently unclear. We have examined in streptozotocin-diabetic rats the permeability of the blood-brain barrier at the level of 12 discrete brain regions employing 3 intravenous tracers of different molecular weight: sucrose, insulin and horseradish peroxidase. In animals killed 5 min after tracer injection both the sucrose and the inulin spaces were similar to controls. In order to assess whether more prolonged circulation of tracers would uncover leakage, we studied brain spaces at longer intervals after tracer injections. When inulin was allowed to circulate for 15 min prior to killing, animals with 4 weeks of diabetes (but not 2 weeks) exhibited larger inulin spaces at the level of the medio-basal hypothalamus (p less than 0.01), medio-dorsal hypothalamus (p less than 0.05) and periaqueductal gray (p less than 0.01). Horseradish peroxidase, even after 75 min of perfusion, remained confined in both diabetic and control animals to central nervous system areas devoid of blood-brain barrier. Thus, after a relatively short duration of diabetes the blood-brain barrier manifests an increased permeability. It is subtle, limited to some brain regions and selective for low molecular weight tracers.