Aquaporin-4 (AQP4) is the major water channel in the brain, expressed predominantly in astroglial cell membranes. Initial studies in AQP4-deficient mice showed reduced cellular brain edema following water intoxication and ischemic stroke. We hypothesized that AQP4 deletion would have the opposite effect (increased brain swelling) in vasogenic (noncellular) edema because of impaired removal of excess brain water through glial limitans and ependymal barriers. In support of this hypothesis, we found higher intracranial pressure (ICP, 52+/-6 vs. 26+/-3 cm H2O) and brain water content (81.2+/-0.1 vs. 80.4+/-0.1%) in AQP4-deficient mice after continuous intraparenchymal fluid infusion. In a freeze-injury model of vasogenic brain edema, AQP4-deficient mice had remarkably worse clinical outcome, higher ICP (22+/-4 vs. 9+/-1 cm H2O), and greater brain water content (80.9+/-0.1 vs. 79.4+/-0.1%). In a brain tumor edema model involving stereotactic implantation of melanoma cells, tumor growth was comparable in wild-type and AQP4-deficient mice. However, AQP4-deficient mice had higher ICP (39+/-4 vs. 19+/-5 cm H2O at seven days postimplantation) and corresponding accelerated neurological deterioration. Thus, AQP4-mediated transcellular water movement is crucial for fluid clearance in vasogenic brain edema, suggesting AQP4 activation and/or up-regulation as a novel therapeutic option in vasogenic brain edema.