Multiple lead systems are shown to have a higher sensitivity than that of single leads for detecting coronary artery disease (CAD) during exercise testing, but the value of ST-segment depression isolated to the inferior leads is questionable. To ascertain the diagnostic accuracy of inferior limb lead II compared with that of precordial lead V 5, a retrospective analysis of 173 men was performed (108 in a training population and 65 in a validation cohort). All patients had a standard exercise test and underwent diagnostic coronary angiography within 15 days of the exercise test (range 1 to 65). Sixty-three patients had ≥ 1 coronary stenoses ≥70%, or left main lesion ≥50%, whereas 45 patients in the training population did not. Exclusion criteria were female sex, left ventricular hypertrophy, left bundle branch block or resting ST-segment depression on the baseline electrocardiogram, previous myocardial infarction or revascularization procedures, and any significant valvular or congenital heart disease. Lead V 5 had a better combination of sensitivity (65%) and specificity (84%) (chi-square = 24.11; p < 0.001) than that of lead II (sensitivity 71%, specificity 44%) (chi-square = 2.25; p = 0.13) at a single cut point, and this improved specificity was substantial (95% confidence interval for observed difference 22 to 58%). Receiver-operating characteristic curve analysis also revealed that lead V 5 (area = 0.759) was markedly superior to lead II (area = 0.582) over multiple cut points (z = 3.032; 2p = 0.002). In fact, the area under the lead II curve (0.582) was not significantly >0.50 (z = 1.465; p = 0.07), suggesting that for the identification of CAD, isolated ST-segment depression in lead II is unreliable. In patients with normal electrocardiograms, precordial lead V 5 is a better marker for CAD during exercise testing than is limb lead II. Exercise-induced ST-segment depression isolated to the inferior leads is of little value.