Hypotension during exercise testing has been considered a marker of extensive coronary artery disease (CAD) and poor prognosis. The mechanism of hypotension was examined in 25 CAD patients who developed hypotension during treadmill exercise testing (mean decrease in systolic blood pressure [BP] 33 ± 13 mm Hg) (group 1) and was compared with the results of 25 CAD patients who had a normal systolic BP response to exercise (mean Increase 53 ± 15 mm Hg) (group 2). The 2 groups were comparable in age, sex, extent of CAD, previous myocardial infarction, left ventricular ejection fraction, history of hypertension and cardiac medications. Exercise heart rate (121 ± 23 vs 133 ± 25 beats/min; p = not significant [NS]) and duration (6 ± 2 vs 7 ± 3 minutes; p = NS) were comparable. ST-segment depression occurred in 44% of patients in group 1 and in 52% in group 2 (p = NS), and angina during exercise occurred in 60% of both groups. Single-photon emission computed tomographic thallium images were abnormal in 24 patients (96%) in group 1 and in 20 patients (80%) in group 2 (p = NS). Percent thallium abnormality was 19 ± 12% in group 1, and 18 ± 14% in group 2 (p = NS), and the severity of thallium abnormality was 710 ± 510 in group 1, and 510 ± 500 in group 2 (p = NS). Ischemia involving the Inferior/posterior segments was seen in 68% of patients in group 1 and in 60% in group 2 (p = NS). Increased lung thallium uptake was seen in 48% of both groups. Thus, exercise-induced hypotension cannot be explained by the extent of CAD or ischemia; it is probably due to ischemic activation of mechanoreceptors, a mechanism similar to those of other types of neurally mediated hypotension. © 1992.