Research protocols often utilize serial exercise testing to examine the efficacy of anti-ischemic therapies. These tests, however, are prone to multiple sources of bias. This investigation sought to determine the influence of varying precordial electrocardiographic (ECG) electrode placement on the detection of exercise-induced ST-segment shifts. Fifteen coronary artery disease patients with abnormal exercise tests were studied. Based on the previous exercise test, the precordial electrode position exhibiting the greatest ST-segment shift was selected as the reference electrode. Four additional electrodes were placed around this reference electrode and exercise testing was performed. ECG strips were recorded every minute. The time-to-onset and -offset of ischemic-type ST-segment depression was recorded. ST-segment depression was recorded during exercise from the reference electrode in 12 of 15 patients. Ischemic-type ST-depression was also recorded in each of these 12 patients with the surrounding electrodes; however, the time-to-onset detected by all four surrounding electrodes concurred in only 5 of 12 (42%) patients. The time-to-offset of the ST-segment depression concurred in 9 of 12 (75%) patients. Serial ECGs recorded from similar but not exactly the same precordial ECG electrode position should yield similar results for the detection of ischemia, but time-to-onset or -offset of ischemia may differ by 60 s or more. Small changes in the time-to-onset and -offset of ischemia should not be considered reliable indicators of anti-ischemia efficacy.