AIMS: Technological advances in cardiac imaging have led to dramatic increases in test utilization and consumption of a growing proportion of cardiovascular healthcare costs. The opportunity costs of strategies favouring exercise echocardiography or SPECT imaging have been incompletely evaluated. METHODS AND RESULTS: We examined prognosis and cost-effectiveness of exercise echocardiography (n = 4884) vs. SPECT (n = 4637) imaging in stable, intermediate risk, chest pain patients. Ischaemia extent was defined as the number of vascular territories with echocardiographic wall motion or SPECT perfusion abnormalities. Cox proportional hazard models were employed to assess time to cardiac death or myocardial infarction (MI). Total cardiovascular costs were summed (discounted and inflation-corrected) throughout follow-up. A cost-effectiveness ratio < Dollars 50,000 per life year saved (LYS) was considered favourable for economic efficiency. The risk-adjusted 3-year death or MI rates classified by extent of ischaemia were similar, ranging from 2.3 to 8.0% for echocardiography and from 3.5 to 11.0% for SPECT (model chi2 = 216; P < 0.0001; interaction P = 0.24). Cost-effectiveness ratios for echocardiography were < Dollars 20,000/LYS when the annual risk of death or MI was < 2%. However, when yearly cardiac event rate were > 2%, cost-effectiveness ratios for echocardiography vs. SPECT were in the range of Dollars 66,686-Dollars 419,522/LYS. For patients with established coronary disease (i.e. > or = 2% annual event risk), SPECT ischaemia was associated with earlier and greater utilization of coronary revascularization (P < 0.0001) resulting in an incremental cost-effectiveness ratio of Dollars 32,381/LYS. CONCLUSION: Health care policies aimed at allocating limited resources can be effectively guided by applying clinical and economic outcomes evidence. A strategy aimed at cost-effective testing would support using echocardiography in low-risk patients with suspected coronary disease, whereas those higher risk patients benefit from referral to SPECT imaging.