Excitatory amino acids and oxygen free radicals have been reported to cooperate in the genesis of brain injury in vivo and in vitro. In this study, we tested the capacity of a noncompetitive N-methyl-D-aspartate receptor antagonist, MK-801, and a 21-aminosteroid, U-74006F, tirilazad mesylate, to block the opening of the blood-brain barrier after subarachnoid injection of FeCl2, which is believed to cause a primarily "pure" free radical insult. Subarachnoid injection of FeCl2 resulted in a significant 10-fold increase in Evans blue extravasation while sham injection or NaCl injection had no effect. Pretreatment with either MK-801 or U-74006F significantly reduced the FeCl2-induced increase in capillary permeability by 43 and 63%, respectively (p < 0.05). Combined treatment with MK-801 and U-74006F resulted in a 65% reduction in vascular leakage that was not significantly greater than pretreatment with either drug alone. These results show that both excitatory amino acids and free radicals can damage the cerebral microvasculature and that an excitatory amino acid antagonist can partially protect the blood-brain barrier after free radical-induced injury.