Increasing numbers of reports demonstrate the importance of iron and oxygen free radicals in brain injury and brain edema. We investigated the protective effects of three different ferric and ferrous iron-chelating agents on cold-induced brain edema. Vasogenic brain edema was produced by a cortical freezing lesion. Thirty-eight cats were separated into five groups: Group 1 (N = 8): normal control group without lesion; Group 2 (N = 8): untreated group; Group 3 (N = 8): deferoxamine (extracellular and intracellular ferric iron chelator)-treated group; Group 4 (N = 8): 2,3-dihydroxybenzoic acid (extracellular ferric iron chelator)-treated group; and Group 5 (N = 6): 2,2-bipyridine (intracellular ferrous iron chelator)-treated group. In Groups 3, 4, and 5, each agent was administered intravenously 15 minutes before lesion production and 60 minutes later. Animals in Groups 2, 3, 4, and 5 were killed 6 hours after lesion production. Brain water content in 8 sampling areas was measured by the specific gravity method. Blood-brain barrier disruption was assessed by the spread of Evans blue dye measured by planimetry. Brain water contents and Evans blue dye extravasated areas were significantly reduced in Groups 3 and 5 in comparison to Groups 2 and 4. These data suggest that both ferrous and ferric iron-chelating agents, which can penetrate the cell membrane and, presumably, act intracellularly, are effective in reducing cold-induced brain edema.