Oxygen-derived free radicals and membrane lipid peroxidation have been postulated to be involved in brain edema and cell death, secondary to ischemia and traumatic injury. Using a model of brain edema induced by cold-induced injury, we have demonstrated an early elevation of superoxide radicals followed by permeability changes in the blood-brain barrier and development of edema in injured brain. Intravenous injection of liposome-entrapped copper-zinc-superoxide dismutase 5 minutes before the injury-enhanced entry of the enzyme into endothelial cells of the blood-brain barrier of injured brain reduced the brain level of superoxide radicals and ameliorated blood-brain barrier permeability changes and brain edema. Identical treatment 5 minutes after injury was also effective. These data demonstrate that superoxide radicals play an important role in the delayed development of vasogenic brain edema following brain injury.