We studied the effects of heparin, given as 12,500 units intravenously, on cardiac metabolism during catheterization of the coronary sinus at rest and during repeated rapid atrial pacing in 8 patients with stable angina pectoris, positive stress tests and coronary arterial disease and in 8 patients with normal coronary arteries without objective signs of ischemic heart disease. Heparin did not influence angina, ST-segment depression or myocardial lactate production induced by pacing in the group with diseased coronary arteries. In both groups, heparin increased the arterial levels (70%) and the myocardial uptake (40-50%) of free fatty acids, the latter only during non-ischemic conditions. Myocardial net uptakes of glucose, lactate and glutamate and the release of alanine were reduced by heparin in the subjects with normal coronary arteries but not in those with ischemic heart disease. Myocardial oxygen consumption was unchanged. In the patients with normal coronary arteries, the levels of free fatty acid in the arteries were positively related to myocardial uptake of fatty acids and the release of citrate but inversely related to cardiac uptake of lactate and glucose. These relations were lacking in the patients with diseased coronary arteries. The metabolic effects of heparin on the heart, therefore, were diminished in patients with ischemic heart disease when compared to controls. This is probably due to an altered regulation of substrate preference in ischemic hearts.