In this study, we tested the hypothesis that myocardial ischemia induced by exercise in patients is associated with diminished metabolism and/or delayed clearance of an intravenously injected fatty acid, iodine 123-labeled phenylpentadecanoic acid (IPPA). Fifteen normal volunteers and 18 patients with significant coronary heart disease (CHD) received IPPA during exercise. In the patients with CHD, radionuclide ventriculograms were also obtained during exercise. The normal volunteers had relatively uniform initial left ventricular segmental IPPA activity after exercise and uniform IPPA clearance in the interval from 4 to 20 min immediately after exercise. In contrast, the patients with CHD had increased initial left ventricular segmental IPPA activity (63%, p < .001) and delayed IPPA clearance (44%, p < .01) in segments supplied by significantly narrowed coronary arteries. Based on analysis with the mean values + 1 SD for initial IPPA activity, clearance, or both in normal volunteers, the sensitivity and specificity of exercise IPPA scintigraphy for detecting CHD were 89% and 67%, respectively; when + 2 SD differences from the mean values in the normal volunteers were considered, the sensitivity and specificity were 72% and 100%, respectively. Among the total of 27 noninfarcted left ventricular segments supplied by significantly narrowed coronary arteries in the study patients, 26 (96%) had an abnormality (mean + 1 SD) of either initial IPPA activity or clearance compared with corresponding segments in the normal volunteers and/or with other left ventricular segments in the same image that were not supplied by significantly narrowed coronary arteries. Thus, these data suggest that IPPA scintigraphy may be used in the identification of myocardial ischemia in patients with CHD by demonstrating abnormal initial left ventricular segmental IPPA activity and/or delayed clearance after exercise.