Abstract We investigated the mechanisms of exercise-induced precordial ST-segment depression on the electrocardiogram in prior inferior myocardial infarction with single-vessel disease and attempted to differentiate the ST-segment depression between single- and multi-vessel disease. Subjects included three groups: group Ia ( n = 11), inferior myocardial infarction with single-vessel disease that showed no precordial ST-segment depression; group Ib ( n = 7), inferior myocardial infarction with single-vessel disease accompanied by precordial ST-segment depression; and group II ( n = 10), inferior myocardial infarction with multi-vessel disease. The subjects underwent 12-lead exercise electrocardiography, stress Tl-201 myocardial imaging and stress radionuclide ventriculography. Exercise-induced precordial ST-segment depression observed in group Ib was associated with large infarction and infarction extending into the inferoseptal wall of the left ventricle on myocardial image. On stress ventriculography, worsening of the septal wall motion was more frequently observed in group Ib than in group Ia. Coronary arteriography revealed a higher rate of rich collateral vessels to the infarcted zone in group Ib than in group Ia. When we compared the diagnostic ability for detecting multi-vessel disease in prior inferior myocardial infarction, although sensitivity was not different among three tests, both exercise electrocardiography and radionuclide ventriculography had poor specificity and predictive value compared to stress Tl-201 myocardial imaging. Thus we concluded that exercise-induced precordial ST-segment depression observed in prior inferior myocardial infarction with single-vessel disease should reflect a peri-infarctional ischemia located in the inferoseptal wall of the left ventricle, and that stress Tl-201 myocardial imaging is the most accurate method for diagnosing multi-vessel disease in prior inferior myocardial infarction.