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Background Dobutamine stress echocardiogram (DSE) is a feasible and safe exercise-independent stress modality for diagnoses of coronary artery disease (CAD), but it is subjective, and operator dependant. Two-dimensional strain at peak stress could overcome these limitations and thus increase the accuracy of DSE. Methods and Results This was a prospective observational study in which 80 patients underwent DSE, two-dimensional strain at peak stress, and coronary angiography. Global longitudinal strains (GLS) cutoff point of −16.75 had 77.42% sensitivity and 83.33% specificity to detect significant CAD. Global circumferential strain (GCS) cutoff point of −20.75 had 93.55% sensitivity and 66.67% specificity to detect significant CAD (P=.003, areas under the curve [AUC]=0.73). The average territorial strain cutoff point for significant left anterior descending (LAD) lesion was −15.4 with 77.78% sensitivity and 82.86% specificity (P=.0001, AUC=0.78) and for non-LAD lesion was −16.9 with 82.93% sensitivity and 53.85% specificity (P=.0009, AUC=0.69). Two-dimensional strain at peak stress showed better agreement than DSE as regard number of vessels affected (K=0.579 vs 0.107), LAD lesion detection (K=0.783 vs 0.438), and non-LAD lesion detection (K=0.699 vs 0.233). Global longitudinal strain (GLS) at peak stress reduced DSE false positivity by 83%; the number of false-positive patients was reduced from 18 patients to only three patients. Conclusion Two-dimensional strain at peak stress had an incremental value over DSE visual assessment/ wall-motion score index (WMSI) in reducing false-positive results of DSE. Two-dimensional strain at peak stress had greater accuracy than DSE alone not only in detection of significant CAD but also in detection of number of vessels with significant lesion as well as CAD localization.