According to a new hypothesis based on epidemiologic observations, iatrogenic maneuvers, natural occurrences, and animal experiments, absolute or relative deficiency of copper is of prime importance in the etiology of ischemic heart disease. Male weanling rats were made copper deficient with a purified diet containing 0.79 microgram Cu/g diet and containing all other nutrients known to be essential. Deficiency was verified by a 39% increase in cholesterolemia. Electrocardiograms of copper-deficient rats showed several abnormalities including S-T segment depression for one-third to one-half of the R-R interval, bundle branch block with R waves three times normal height and width, Q waves, and second- and third-degree heart block. Copper deficiency shortened the lives of the rats by 73%. Copper deficiency is the only nutritional insult that has produced rapid unfavorable alterations in lipid metabolism, cardiac and arterial anatomy, and cardiac electrophysiology. Copper metabolism may be important in the etiology of ischemic heart disease and in the arrhythmias associated with the consumption of liquid-protein diets.