Background The clinical significance of exercise-induced chest pain remains controversial, as reflected by sharply discordant clinical results within the medical literature. Thus, we developed a prospective study to compare the functional significance of silent versus symptomatic ischemia and to evaluate whether patient selection biases influence this analysis.Methods and Results We evaluated 117 patients (mean age, 63+-9 years) with ischemic ST-segment depression during treadmill testing. Each patient underwent Tl-201 myocardial perfusion single-photon emission computed tomography (SPECT) after exercise followed by 24-ambulatory ECG monitoring. Patients were divided into silent versus symptomatic cohorts and were compared for the degree of hemodynamic, exercise and ambulatory ECG, and thallium abnormalities during stress testing. Analyses were repeated as the patient population became increasingly restricted. Compared with the silent patients, patients with chest pain during exercise had a shorter exercise duration (P<.009), lower peak heart rate (P=.009) and double product (P=.005), lower heart rate threshold for ST depression (P<.05), more episodes of ambulatory ST-segment depression (P<.05), a higher frequency of ischemia abnormalities during Tl-201 SPECT (P=.02), and higher summed Tl reversibility scores (P=.002). As the population became increasingly restricted, the relative magnitude of differences in silent versus symptomatic cohorts diminished, whereas the absolute magnitude of ischemic abnormalities progressively increased in both cohorts. For example, within the restricted group having ischemia on both exercise and ambulatory ECG, 50% of the silent cohort had severe ischemia on Tl SPECT (five or more reversible defects) and more than one third demonstrated the ominous finding of transient left ventricular dilation after exercise.Conclusions The induction of chest pain is associated with substantially more functional abnormalities when it is analyzed in a relatively "broad-spectrum" coronary artery disease population; by contrast, chest pain tends to lose its apparent value as a clinical test parameter when its analysis is restricted to coronary artery disease populations with a greater a priori likelihood of manifesting inducible ischemia. These findings may help resolve some of the previous discordant literature reports. (Circulation. 1994;89:1958-1966.)