OBJECTIVE This study was conducted to determine whether the long-term administration of fish oil attenuates myocardial necrosis in an occlusion-reperfusion model of myocardial ischemia. BACKGROUND Omega-3 fatty acids found in fish oil have various biologic properties that may modify myocardial injury caused by severe ischemia and reperfusion. METHODS Of 21 dogs fed an identical diet, 10 were given supplemental fish oil containing 0.06 g/kg per day of eicosapentaenoic acid for 6 weeks. Under anesthesia and open chest conditions, the left circumflex coronary artery was occluded for 90 min, followed by 6 h of reperfusion. Regional myocardial blood flow was measured with 15-microns spheres before and during occlusion and during reperfusion. The area at risk and infarct size were measured using standard staining techniques. RESULTS In the dogs receiving supplemental fish oil, the platelet cell membrane content of eicosapentaenoic acid increased from 0.9 +/- 0.56% to 7.1 +/- 4.0% (p < 0.001). Infarct size was 29 +/- 7% in the control group and 13 +/- 3% in the fish oil group (p < 0.05). There was no significant difference in the myocardial area at risk or rate-pressure product between the control and fish oil groups. There was no difference in regional myocardial blood flow between the groups at baseline study or during coronary occlusion and reperfusion. CONCLUSIONS Dietary fish oil supplementation significantly reduced myocardial infarct size in this model. The difference in infarct size did not appear to be related to dissimilarities in regional myocardial blood flow or determinants of oxygen consumption. Further investigation is needed to determine the nature of the protective mechanisms of omega-3 fatty acids on myocardial infarct size.