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Objectives: The purpose of this study was to evaluate whether the addition of a contrast agent to dobutamine stress echocardiography (DSE) improves its diagnostic accuracy for coronary artery disease (CAD) and to determine the effect of image quality on the diagnostic impact of contrast agent use in this setting. Background: Contrast agents can improve endocardial border definition. To date, however, there are no randomized trials that have evaluated the impact of contrast agent use on the accuracy of DSE. Methods: Patients referred for stress testing with dobutamine echocardiography underwent 2 DSE studies: 1 with and 1 without a contrast agent, at least 4 h apart in a randomized order and within a 24-h period. Results: A total of 101 patients underwent both DSE studies. Similar hemodynamics were achieved during the 2 stress testing sessions. The use of a contrast agent improved the percentage of segments adequately visualized at baseline (from 72 ± 24% to 95 ± 8%) and more so at peak stress (67 ± 28% to 96 ± 7%); both p < 0.001. Interpretation of wall motion with high confidence also increased with contrast agent use from 36% to 74% (p < 0.001). Segment visualization with the use of a contrast agent improved in all views, but was more pronounced in the apical views. In unenhanced DSE, 36% of studies were normal, 51% had ischemia, and 8% were uninterpretable—all of which became interpretable with the use of a contrast agent. When compared with angiography (n = 92; 55 patients with CAD), accurate detection of ischemia was higher with contrast-enhanced studies versus nonenhanced studies (p = 0.02). As endocardial visualization and confidence of interpretation decreased in unenhanced studies, a greater impact of the use of a contrast agent on DSE accuracy was observed (p < 0.01). Conclusions: During dobutamine stress echocardiography, contrast agent administration improves endocardial visualization at rest and more so during stress, leading to a higher confidence of interpretation and greater accuracy in evaluating CAD. The lesser the endocardial border visualization, the higher the impact of contrast echocardiography on accuracy. [Copyright &y& Elsevier]