Arterial oxygen tension is variable in patients with acute myocardial infarction, and the effect of hypoxemia on the extent of myocardial necrosis after coronary occlusion has not been defined. In 11 anesthetized open chest dogs the left anterior descending coronary artery or one of its major branches was occluded for 20 minutes, and 10 to 15 epicardial electrocardiographic leads were recorded in the distribution and vicinity of the site of occlusion. Average S-T segment elevation and the number of sites showing S-T segment elevation greater than 2 mv, 15 minutes after occlusion were used as indexes of the severity and extent of ischemic injury. After occlusion with an inspired oxygen concentration of 20 percent these indexes were, respectively, 2.0 plus or minus 0.5 mv (mean plus or minus standard error) and 3.6 plus or minus 0.8 sites; the respective values increased to 3.3 plus or minus 0.5 mv (P smaller than 0.01) and 6.7 plus or minus 0.7 sites (P smaller than 0.01) after occlusion with an inspired oxygen concentration of 10 percent, and arterial partial pressure of oxygen decreased from 92 plus or minus 5 to 45 plus or minus 3 mm Hg. In 23 dogs the occlusion was maintained for 24 hours and the S-T segment elevation 15 minutes after occlusion was compared with myocardial creatine phosphokinase (CPK) activity and histologic appearance 24 hours later. In control dogs (inspired oxygen concentration of 20 percent) sites with no S-T segment elevation 15 minutes after occlusion showed normal myocardial CPK activity 24 hours later, whereas in sites with S-T segment elevation exceeding 2 mv there was an inverse relation between S-T segment elevation in each site and its myocardial CPK activity 24 hours later. Histologic examination revealed early myocardial necrosis in 98 percent (82 of 84) of sites with S-T segment elevation greater than 2 mv. In experimental dogs (inhaling a 10 percent oxygen concentration for the first 8 of the 24 hours of occlusion) many sites that showed no S-T segment elevation before hypoxemia was induced exhibited S-T segment elevation before hypoxemia was induced exhibited S-T segment elevations 30 minutes later and showed abnormally low CPK activity and histologic evidence of early necrosis. We conclude that after experimental coronary occlusion, hypoxemia is deleterious because it substantially increases myocardial damage.