We investigated to what extent the antioxidative hydroxystilbene oxyresveratrol (trans-2,3′,4,5′-tetrahydroxystilbene, OXY), that we showed earlier to be strongly neuroprotective in a stroke model, may cross the blood-brain barrier (BBB) in healthy rats and in subjects submitted to focal infarction. Tissue extraction and in vivo microdialysis in the striatum show that systematically applied OXY is able to penetrate the BBB in control animals, but to a low extent. Microdialysis samples from animals that were subjected to a middle cerebral artery occlusion (MCAO) displayed strongly increased OXY levels (more than six-fold) in the infarct region as compared to sham-operated rats. Our data show that OXY may exert direct protective effects in the brain by crossing the BBB and may prove an excellent complementary drug for the treatment of neurodegenerative disorders that causally involve oxidative/nitrosative stress, especially in stroke. © 2005 Elsevier Ireland Ltd. All rights reserved.