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Background: If compared with two-dimensional echocardiography (2DE), quantitative myocardial contrast echocardiography (MCE) improves detection of coronary artery disease (CAD) during pharmacological stress, but there is paucity of data regarding quantitative MCE performed during supine bicycle stress. Objectives: To determine the feasibility and accuracy of quantitative MCE and assess its incremental benefit over 2DE for detection of CAD during supine bicycle stress. Methods: Sixty-one consecutive patients (47 males, 14 females, mean age 57 ± 12 years) with suspected CAD, who were scheduled for coronary angiography, underwent 2DE and MCE supine bicycle stress. The diagnosis of obstructive CAD (≥50% stenosis) was based on inducible wall-motion and myocardial perfusion abnormalities. For quantitative myocardial perfusion analysis, A, β, and Aβ reserve were derived from myocardial contrast replenishment curves. Results: Quantitative coronary angiography revealed ≥50% stenosis in 41, ≥70% stenosis in 18, single vessel disease in 24, and multivessel disease in 17 patients. If compared with 2DE, quantitative MCE was more sensitive (71% vs. 93%; P < 0.05) and more accurate (74% vs. 89%; P < 0.05) to detect obstructive CAD. The sensitivity of 2DE and quantitative MCE was 61% and 91% (P < 0.05) in 50–69% stenosis, and 63% and 92% (P < 0.05) in single vessel disease. No difference in sensitivity between 2DE and quantitative MCE was found in subjects with ≥70% stenosis (83% vs. 94%, P = NS) and multivessel disease (82% vs. 94%, P = NS). Conclusions: Quantitative MCE enhances sensitivity and accuracy of supine bicycle stress 2DE for detection of obstructive CAD, and this incremental benefit is especially present in less severe disease. (Echocardiography 2013;30:392-400).