The involvement of corticosteroids in stress-induced change in blood-brain barrier (BBB) permeability was investigated. Mice were adrenalectomized and administered with pyridostigmine bromide (PB) or Evan's blue, markers of BBB penetration, followed by 18-h cold-restraint stress (CRS). Rats were administered with mifepristone, a corticosteroid receptor blocker, and the markers, followed by 4-h water immersion-restraint stress (WIRS). Separately, soman was administered to induce seizures-mediated BBB opening. CRS did not induce PB and Evan's blue penetration, which were not affected by adrenalectomy. Also, the markers were not detected in the brain of rats subjected to WIRS, regardless of the treatment of mifepristone. In comparison, 1-h epileptic seizures increased the penetration of Evan's blue by 875%. The results suggest that in contrast to seizure-related BBB opening, profound stresses do not practically increase the BBB permeability, and that corticosteroids are not involved in the stress-induced BBB penetration of charged chemicals and albumin-dye complex.