In the dog, osmotic opening of the blood-brain barrier (BBB) in the posterior circulation via the vertebral artery and in the anterior circulation via the internal carotid artery was utilized to increase the delivery of three substances of varying molecular weight to the central nervous system. The cerebrospinal fluid (CSF) concentration of all three agents dramatically increased after BBB opening. In contrast to methotrexate, Evans blue-albumin and monoclonal antibody (MAb) concentrations in CSF were 6-fold greater when given after posterior rather than anterior circulation BBB opening. Conversely, MAb delivery to brain parenchyma was optimized after osmotic BBB modification via the carotid artery. This suggests that, with higher molecular weight substances, osmotic barrier opening has a differential effect on the blood-brain vs. blood-CSF barriers.