Ortho-iodo sodium benzoate (OISB) decreases the affinity of blood for oxygen, thus enhancing potential tissue oxygen delivery. To test the hypothesis that a change in oxygen affinity would ameliorate regional myocardial ischemic injury resulting from occlusion of the left anterior descending (LAD) coronary artery, experiments were carried out in 55 anesthetized dogs which received an intravenous infusion of OISB. In Protocol I studies (n = 9), preocclusion intravenous infusion of OISB (500 mg/kg) reduced epicardial S-T segment elevation 15 minutes after coronary occlusion, while a similar volume of normal saline solution did not affect this index of ischemic damage. In Protocol II experiments, 34 dogs were randomized to either an OISB or saline group, after which the LAD was ligated, the chest closed, and the animal allowed to recover from anesthesia. Myocardial infarction (MI) size was assessed after the animal died or was killed 8 to 24 hours later, and was found to be 29% smaller in dogs receiving OISB. In 6 dogs, blood P50 (the partial oxygen pressure at which hemoglobin is 50% saturated with oxygen) was increased by OISB infusion, confirming that its administration effected a rightward shift in the oxyhemoglobin dissociation curve. Protocol III studies assessed the effects of OISB on cardiac hemodynamic function and acute myocardial ischemic damage when infusion was begun 15 minutes after LAD occlusion: average epicardial S-T segment elevation was not altered by saline solution, but decreased when OISB was infused during the last 15 minutes of myocardial ischemia. Reductions in heart rate, left ventricular dP/dt, and cardiac output were observed in 7 dogs during OISB infusion, but there were no changes in these measurements during coronary occlusion in 5 dogs receiving a constant infusion of saline solution. There were no changes in regional myocardial blood flow (microsphere technique) to either ischemic or nonischemic zones in either the saline control or OISB treatment groups. Thus, both acute myocardial ischemic injury (assessed by epicardial electrocardiographic mapping) and ultimate MI size are reduced when OISB is infused before experimental coronary artery occlusion. OISB also reduces myocardial ischemic injury when its administration is begun 15 minutes after coronary occlusion, while effecting decreases in heart rate, left ventricular contractility, and cardiac output.