The lamprey (Entosphenus japonicus Martens) has been recommended in Japan as an efficacious diet for curing some of chronic inflammatory disorders. Fresh lamprey is rich in n-3 unsaturated fatty acids (e.g., eicosapentaenoic and docosahexaenoic acids) with minimal seasonal variation. The dietary effect of lamprey oil on acute myocardial ischemia was therefore investigated. Rats were fed a control diet or a diet supplemented with 5% safflower oil (SO) or 5% lamprey oil (LO) for 4 weeks. After coronary artery ligation, rats fed the LO diet demonstrated a higher 24-h survival rate and a reduced loss of creatine kinase activity from ischemic myocardium when compared with rats fed the control or SO diet. Moreover, the intracellular redistribution of lysosomal enzyme activity in the ischemic myocardium was significantly suppressed in the LO diet group. Analysis of the fatty acid composition of myocardial phospholipids in rats fed LO showed marked elevation of n-3 fatty acids, whereas arachidonic acid (n-6) content was significantly reduced. Hence, the n-3/n-6 ratio of myocardial phospholipids was markedly increased in the LO diet group. In addition, there was more than a 77% reduction in TXB2 synthetic capacity in whole blood in rats fed the LO diet when compared with rats fed either the control or SO diet. In conclusion, dietary supplementation with LO prevents sudden cardiac death and limits the extension of cellular damage from acute myocardial ischemia in rats. Both changes in thromboxane generation and altered membrane fatty acid composition may be involved in the observed reduction of ischemic damage in the heart.