Cerebral edema develops after anoxic brain injury. In two models of asphyxial and asystolic cardiac arrest without resuscitation, we found that edema develops shortly after anoxia secondary to terminal depolarizations and the abnormal entry of cerebrospinal fluid (CSF). Edema severity correlated with the availability of CSF with the age-dependent increase in CSF volume worsening the severity of edema. Edema was identified primarily in brain regions bordering CSF compartments in mice and humans. The degree of ex vivo tissue swelling was predicted by an osmotic model suggesting that anoxic brain tissue possesses a high intrinsic osmotic potential. This osmotic process was temperature-dependent, proposing an additional mechanism for the beneficial effect of therapeutic hypothermia. These observations show that CSF is a primary source of edema fluid in anoxic brain. This novel insight offers a mechanistic basis for the future development of alternative strategies to prevent cerebral edema formation after cardiac arrest.