Patients with coronary artery disease may not manifest ST segment depression during exercise. Inadequate stress, mild coronary artery disease and severe left ventricular dysfunction have been postulated as mechanisms. The purpose of this study was to determine the influence of exercise R wave amplitude on ST segment depression in 81 patients with coronary artery disease (50% or greater diameter narrowing of one or more vessels). All patients underwent symptom-limited treadmill exercise testing and 71 patients (88%) had concomitant thallium-201 imaging. In 26 patients, the exercise R wave amplitude in electrocardiographic lead V5 was less than 11 mm (Group I), and in 55 patients it was 11 mm or greater (Group II). The two groups were similar with regard to age, sex, propranolol administration and left ventricular function. There was a significant difference in the incidence of positive exercise electrocardiograms in the two groups (2 patients [8%] in Group I and 27 patients [49%] in Group II; p = 0.002), despite similar exercise heart rate and extent of coronary artery disease. Myocardial ischemia, manifested by exercise-induced angina or exercise-induced thallium-201 perfusion defects, was similar in both groups. Thallium-201 imaging showed perfusion defects in 73% of patients in Group I and in 76% of patients in Group II (p = not significant). Thus, R wave amplitude is a new determinant of failure to develop ST depression during exercise. A low R wave amplitude (less than 11 mm) is rarely associated with ST depression, even in patients with multivessel coronary artery disease. Exercise thallium-201 imaging is a valuable diagnostic tool in patients with low R wave amplitude.