Basic and clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) decrease fatal arrhythmias and infarct sizes. This study investigated if pericardial delivery of n-3 PUFAs would protect the myocardium from ischemic damages and arrhythmias. Acute myocardial infarctions were induced in 23 pigs with either 45 min balloon inflations or clamp occlusions of the left anterior descending coronary arteries and 180 min reperfusion. Docosahexaenoic acid (C22:6n-3, DHA, 45 mg), one of the main n-3 PUFAs in fish oil, was infused within the pericardial space only during the 40 min stabilizing phase, 45 min ischemia and initial 5 min reperfusion. Hemodynamics and cardiac functions were very similar between the DHA-treated (n=11) and control (n=12) groups. However, DHA therapy significantly reduced infarct sizes from 56.8 ± 4.9% for controls to 28.8 ± 7.9% (p < 0.01) for DHA-treated animals. In addition, the DHA-treated animals elicited significantly lowered heart rates and reduced ventricular arrhythmia scores during ischemia. Further, three (25%) control animals experienced 8 episodes of ventricular fibrillation (VF), and 2 died subsequent to unsuccessful defibrillation. In contrast, only one (9%) of eleven DHA-treated pigs elicited one episode of VF which was successfully converted via defibrillation to normal rhythm; thus mortality was reduced from 17% in controls to 0% in DHA-treated animals. These data demonstrate that pericardial infusion of DHA can significantly reduce both malignant arrhythmias and infarct sizes in a porcine infarct model. Pericardial administration of n-3 PUFAs could represent a novel approach to treating or preventing myocardial infarctions.