Technetium-99m (Tc-99m) tetrofosmin single-photon emission computed tomography (SPECT) is a useful alternative to thallium-201 scintigraphy for the assessment of myocardial perfusion. This study assessed the incremental value of exercise Tc-99m tetrofosmin SPECT for the prediction of cardiac events in patients with known or suspected coronary artery disease. Exercise Tc-99m tetrofosmin SPECT imaging was performed in 655 consecutive patients. Follow-up was successful in 648 patients (98.9%). Ten patients underwent early coronary revascularization and were excluded. End points were cardiac death, nonfatal infarction, and late (>60 days) coronary revascularization. An abnormal study was defined as the presence of fixed and/or reversible perfusion defects. A summed stress score (SSS) was derived to estimate the extent and severity of perfusion defects. An abnormal scan was detected in 344 patients (54%). During a mean follow-up period of 4 +/- 1.3 years, 56 patients (9%) died (22 cardiac deaths). Nonfatal myocardial infarction occurred in 19 patients (3%), and 89 patients (14%) underwent late coronary revascularization. An abnormal scan was an independent predictor of cardiac death (hazard ratio 3.5, confidence intervals [CI] 1.1 to 12.2) and provided incremental information over clinical and exercise test data (log-likelihood -133 to -125, p <0.05). The SSS provided incremental prognostic information over clinical data as well (log-likelihood -133 to -127, p <0.05) (hazard ratio 1.23, CI 1.10 to 1.38). An abnormal scan (hazard ratio 3.3, CI 1.1 to 12.2)) and the SSS (hazard ratio 1.25, CI 1.07 to 1.45)) were powerful independent predictors of the combined end point of any cardiac event. Thus, exercise Tc-99m tetrofosmin myocardial perfusion SPECT provides information incremental to clinical data for the prediction of cardiac events in patients with known or suspected coronary artery disease.