Whether adenosine myocardial perfusion single-photon emission computed tomography (SPECT) remains accurate for detecting coronary artery disease (CAD) in the absence of peripheral hemodynamic changes is unknown. To assess the hemodynamic correlates of perfusion defects, we studied 222 consecutive patients (age 71 ± 11 years) without prior myocardial infarction or revascularization who underwent adenosine technetium (Tc)-99m sestamibi myocardial perfusion SPECT and cardiac catheterization within 6 months of adenosine study. The SPECT protocol used separate acquisition of rest thallium-201 and adenosine Tc-99m sestamibi, which was semiquantitatively analyzed in 20 segments with a visual 5-point scoring system (0 = normal, 4 = absent uptake). The overall sensitivity, specificity, and predictive accuracy of adenosine Tc-99m sestamibi SPECT for detecting significant CAD were 93% (159 of 171), 73% (37 of 51), and 88% (196 of 222), respectively. The study population was grouped into 6 categories as a function of peripheral hemodynamic changes: (1) increase in heart rate by ≤10 beats/min (n = 135); (2) increase in heart rate by > 10 beats/min (n = 87); (3) decrease in systolic blood pressure by ≤10 mm Hg (n = 108); (4) decrease in systolic blood pressure by > 10 mm Hg (n = 114); (5) increase in heart rate by ≤ 10 beats/min and decrease in systolic blood pressure by ≤ 10 mm Hg (n = 72); and (6) increase in heart rate by >10 beats/min or decrease in systolic blood pressure by >10 mm Hg (n = 150). The sensitivity, specificity, and predictive accuracy of adenosine sestamibi SPECT were similar in all 6 categories. The prevalence of left main or multivessel CAD and extent of scan abnormality were also similar among all groups. Thus, the diagnostic accuracy of adenosine Tc-99m sestamibi SPECT is high in patients with or without peripheral hemodynamic evidence of adenosine effect.