We have investigated the effect of elevated n-3 (omega-3) fatty acid content in the diet on arrhythmias, ischemic damage, and inflammatory cell infiltration into the reperfused left ventricular free wall (LVFW). Weanling rats were fed purified diets in which the lipid was replaced with either corn oil (CO) or menhaden oil (MO). After 4 wk, MO feeding resulted in significant elevations in both the ratio of n-3 to n-6 fatty acids and the unsaturation index in myocardial phospholipids. Rats were subjected to 15 min of ischemia followed by reperfusion. After 6 h of reperfusion of the left coronary artery there was significantly less creatine kinase (CK) lost from the LVFW of rats fed MO. Leukocyte infiltration into the LVFW, as measured by myeloperoxidase (MPO) activity, was also significantly reduced with MO feeding at 6 h. Arrhythmias were studied in a separate group of 17 rats; both the incidence and severity of ventricular tachycardia and ventricular fibrillation were significantly reduced during the ischemic and reperfusion periods with MO feeding. After 24 h of reperfusion there was also significantly less CK lost from the LVFW of MO-fed rats; however, there was no significant difference in tissue MPO activity in ventricular homogenates. Survival after 24 h of reperfusion was 76% (16/21) for MO- and 41% (9/22) for CO-fed rats. The data suggest a protective effect for dietary MO in myocardial ischemia-reperfusion, which may involve both an early reduction in leukocyte infiltration and a reduction in the incidence of fatal arrhythmias.