Although dobutamine–atropine stress echocardiography (DASE) is an established method for evaluating patients who have coronary artery disease (CAD), it can increase test duration and a patient's exposure to large doses of dobutamine. New protocols, including the early injection of atropine during dobutamine stress echocardiography (EA-DSE), have been proposed to decrease test duration. This study compared the safety, efficacy, and accuracy of EA-DSE with those of DASE. We retrospectively evaluated 3,163 patients who underwent DASE and 1,664 patients who underwent EA-DSE over a period of 12 years. In EA-DSE, atropine at a dose ≤2 mg was started with 20 μg/kg/min of dobutamine if heart rate was <100 beats/min. Diagnostic accuracy for detecting CAD (>50% stenosis) was assessed in patients who underwent quantitative angiography ≤3 months of stress testing. The dobutamine dose used in EA-DSE was smaller than that used in DASE (31 ± 6 vs 36 ± 6 μg/kg/min, p <0.0001), although the atropine dose was larger (0.8 ± 0.5 vs 0.5 ± 0.25 mg, p <0.0001). EA-DSE resulted in a significantly shorter duration of dobutamine infusion (12.4 ± 2.0 vs 14.6 ± 2.5 minutes, p <0.0001), more diagnostic studies (88% vs 81%, p <0.0001), and a lower incidence of minor adverse effects than did DASE. The rate of major adverse effects was similar in the 2 protocols. Sensitivities, specificities, positive predictive values, negative predictive values, and accuracies for detecting CAD were 84%, 90%, 93%, 76%, and 86% for EA-DSE and 86%, 78%, 84%, 79%, and 82% for DASE, respectively (p = NS). Therefore, EA-DSE is a safe and effective alternative to DASE and had a similar accuracy for the detection of CAD.