OBJECTIVES: This study hypothesized that ischemia and atherosclerosis assessment by ultrasound (US) may provide incremental prognostic information in patients with new-onset chest pain who do not have coronary artery disease (CAD). BACKGROUND: The clinical significance of atherosclerosis assessment by carotid US in patients undergoing stress echocardiography (SE) in such patients is unknown. METHODS: Consecutive patients with suspected angina but no history of CAD underwent simultaneous SE and US prospectively to assess myocardial ischemia and carotid plaque burden (CPB), respectively. Patients were followed up for major adverse events (MAEs)-all-cause mortality, nonfatal myocardial infarction, and unplanned coronary revascularization. RESULTS: Of 591 recruited patients, 580 (men, 46%; mean age 59 ± 11 years) patients were available for follow-up. SE demonstrated myocardial ischemia in 12%, but prevalence of carotid plaques was 59%. During a mean follow-up of 1,117 ± 361 days, 40 first MAEs occurred. In the multivariable regression model, pre-test probability (PTP) of CAD (p = 0.001), abnormal SE (p < 0.0001), and CPB (p < 0.0001) predicted MAEs. MAE rates per year increased from 0.9% versus 1.97% versus 4.3% versus 9.7% in patients with no carotid plaque and normal SE versus patients who had plaque and normal SE versus those with no plaque and abnormal SE versus patients with plaque and abnormal SE, respectively (p < 0.0001). In hierarchical analysis, plaque burden provided incremental prognostic value over PTP of CAD and SE; likewise, SE was incremental to PTP-CAD and CPB (p < 0.0001 for both). CONCLUSIONS: In patients with suspected stable angina without known CAD, simultaneous SE (for ischemia) and US (for atherosclerosis) provided incremental prognostic value.