We studied the recovery of retinal pigment epithelium and retinal function after 80 minutes of pressure-induced ischemia in rabbits. Just before restoring circulation, we gave intravenous mannitol (an osmotic agent and free-radical scavenger), dextromethorphan (an N-methyl-D-aspartate receptor antagonist), or catalase (an antioxidant enzyme). Mannitol has not previously been shown to be protective for retinal or retinal pigment epithelial ischemia. At 24 hours after reperfusion, the electroretinogram b-wave was reduced to 37% of preischemic amplitude in untreated eyes, but it recovered to 67% to 80% after treatment with all three agents. The c-wave was replaced by a negative slow PIII response in control eyes and in seven of 12 catalase-treated eyes, but it recovered by 58% to 82% in the remaining catalase-treated eyes and all the mannitol- and dextromethorphan-treated eyes. Histologic examination confirmed that retinal pigment epithelium as well as retina had been damaged by the ischemia. The effects of mannitol seem of special interest, since the drug has a dual mechanism of action and is clinically available.