To determine the significance of ST-segment depression during adenosine perfusion imaging for predicting future cardiac events, 188 patients with interpretable electrocardiograms were assessed 1 to 3 years (mean 21.5 +/- 6.6 months) after adenosine testing. At least 1 mm of ST-segment depression was observed in 32 (17%) patients, with > or = 2 mm of ST-segment depression in 10 (5.3%). Thirty-seven cardiac events occurred during the study period: 2 cardiac deaths, 5 nonfatal myocardial infarctions, 6 admissions for unstable angina, and 24 revascularizations. Univariate predictors of events were a history of congestive heart failure, previous non-Q-wave myocardial infarction, previous coronary angioplasty, use of antianginal medication, ST-segment depression during adenosine infusion (particularly > or = 2 mm), any reversible perfusion defect, transient left ventricular cavity dilation, and the severity of perfusion defects. Multivariate analysis identified > or = 2 mm ST-segment depression as the most significant predictor of cardiac events (relative risk [RR] = 6.5; p = 0.0001). Other independent predictors of events were left ventricular dilation (RR = 3.8; p = 0.002), previous coronary angioplasty (RR = 3.3; p = 0.001), a history of non-Q-wave myocardial infarction (RR = 2.3; p = 0.01), and the presence of any reversible defect (RR = 2.0; p = 0.05). We conclude that ST-segment depression occurs uncommonly during adenosine infusion, but the presence of > or = 2 mm of ST-segment depression is an independent predictor of future cardiac events and provides information in addition to that obtained from clinical variables and the results of adenosine perfusion imaging.