This investigation assesses whether the size of an acutely revascularized myocardial infarct (MI) could be reduced by altering the composition of the initial reperfusate. Nineteen open-chest dogs underwent 4-hour occlusion of the left anterior descending coronary artery and were then assigned to a treatment group: 12 dogs to selective intracoronary infusion of the modified reperfusate over 30 minutes before resumption of blood flow for 60 minutes and 7 to a control group (90 minutes of unmodified blood reperfusion). The modified reperfusate consisted of 500 ml of a fluorocarbon-oxygenated crystalloid solution (PO2 650 mm Hg; total O2 content 5.5 vol%) whose composition was adjusted by decreasing Ca++ (0.25 mM), increasing pH (7.60) and adding glucose (1.8 g/liter). Four hours after occlusion, technetium-99m-labeled microspheres were injected into the left atrium. After 90 minutes of reperfusion, the heart was removed and sliced transversely. Areas riot perfused by microspheres (areas at risk) were traced, planimetered and compared with the areas of necrosis after incubation in triphenyltetrazolium chloride. Areas were then converted into weights. In control dogs, the weight of necrotic myocardium was not significantly different from the weight at risk (5.0 ± 0.7 vs 7.0 ± 0.8 g, respectively [mean ± standard error of the mean]), whereas it was markedly reduced in treated dogs (5.9 ± 0.5 vs 9.4 ± 0.7 g, respectively, p < 0.001). The weight of salvaged myocardium was 3.4 ± 0.5 g in treated dogs vs 1.9 ± 0.4 g in the control group (p < 0.02). When the dogs were classified according to the amount of left ventricle at risk, the protective effects of the modified reperfusate were apparent mainly in the largest areas at risk (> 40% of the left ventricle). We conclude that a modified initial reperfusate can significantly reduce MI size, possibly by preventing some reperfusion-related damage in the reversibly injured myocardial areas, and fluorocarbons are effective in oxygenating such crystalloid reperfusion solutions that might enhance the beneficial effects of intracoronary fibrinolysis. © 1984.