To assess the efficacy of the perfluorochemical Fluosol-DA 20% for myocardial protection during repeated periods of balloon occlusion of the left circumflex coronary artery, 25 anesthetized dogs were randomized to receive either oxygenated perfluorochemical, (Fluosol-DA [F]; n = 10) or oxygenated Ringer's lactate (R; n = 6), at the rate of 30 ml/min, during inflation of the balloon. A control group (C; n = 9) received no infusion. A total of eight inflations were performed, each lasting 90 seconds, followed by an equivalent deflation time. Hemodynamics, ECGs, regional myocardial function, and biochemical parameters were studied. Significant differences were noted in ST segment elevation at 90 seconds of inflation in the F (1.5 mm +/- 0.6), C (3.7 mm +/- 0.75), and R (2.9 mm +/- 0.75) groups (F vs C or R p less than 0.05). This was associated with significant improvement in radial shortening in the jeopardized zone at 45 seconds into occlusion in the F group compared to the C and R groups (F = 21.1% +/- 5.1 vs C = 3.5% +/- 4.5 or R = 1.1% +/- 3.2; p less than 0.05). Results of electron microscopy showed reversible changes of ischemia within the mitochondria, and these were most marked in the C and R groups compared to the F group. Endothelial swelling was mild and was present only focally in the R and C groups. Thus perfluorochemicals may enhance the safety and efficacy of balloon angioplasty.