The effect of exercise-induced myocardial ischemia on cardiopulmonary blood volume was evaluated in patients with coronary artery disease during upright exercise stress testing. Regional pulmonary and cardiac blood volumes were monitored with a multicrystal positron camera positioned over the chest during maximal exercise on a bicycle ergometer. Inhaled carbon monoxide (< 10 ppm) labeled with cyclotronproduced carbon-il (11C) (half-life 20.3 minutes) was used to label the blood with 11C-carboxyhemoglobin. Regional 11C activity was measured over the heart and lungs during rest, exercise and recovery periods, and blood volume was calculated from regional 11C activity compared with the specific activity of a reference venous blood specimen. For patients developing angina pectoris and electrocardiographic ST-segment depression (ischemic group, n = 9), blood volume increased 18.7 ± 6.3% (SEM) (p < 0.01) over the upper lung fields and 15.4 ± 6.8% (p < 0.05) over the lower lung fields at peak exercise. Conversely, for patients without angina or ST-segment depression at peak exercise (nonischemic group, n = 7), the regional pulmonary blood volume was unchanged over both upper and lower lung fields. The cardiac blood volume rose 6.1 ± 2.6% (p < 0.05) for the former group of patients and declined 10.6 ± 5.7% (p < 0.05) for the latter group at peak exercise. Coronary arteriography revealed double- or triple-vessel coronary disease in all patients in the ischemic group and normal coronary arteries or single-vessel disease in the nonischemic group. These data indicate that an ischemic response to exercise stress testing is associated with a transient rise in pulmonary and cardiac blood volume, which may be due to ischemia-induced left ventricular dysfunction.