Background - The incremental value and cost-effectiveness of stress single photon emission computed tomography (SPECT) is of unclear added value over clinical and exercise treadmill testing data in patients with normal resting ECGs, a patient subset known to be at relatively lower risk. Methods and Results - We identified 3058 consecutive patients who underwent exercise dual isotope SPECT, who on follow-up (mean, 1.6±0.5 years; 3.6% lost to follow-up) were found to have 70 hard events (2.3% hard-event rate). Survival analysis used a Cox proportional hazards model, and cost-effectiveness was determined by the cost per hard event identified by strategies with versus without the use of SPECT. In this cohort, a normal study was associated with an exceedingly low hard-event rate (0.4% per year) that increased significantly as a function of the SPECT result. After adjusting for pre-SPECT information, exercise stress SPECT yielded incremental value for the prediction of hard events (Χ2 52 to 85, P<0.001) and significantly stratified patients. In patients with intermediate to high likelihood of coronary artery disease after exercise treadmill testing, a cost-effectiveness ratio of $25 134 per hard event identified and a cost of $5417 per reclassification of patient risk were found. Subset analyses revealed similar prognostic, and cost results were present in men, women, and patients with and without prior histories of coronary artery disease. Conclusions - Stress SPECT yields incremental prognostic value and enhanced risk stratification in patients with normal resting ECGs in a cost-effective manner. These findings are opposite those of previous studies examining anatomic end points in this same population and thus, if confirmed, have significant implications for patient management.