Objective: The ability of multidetector computed tomography (MDCT) to detect stress-induced myocardial perfusion abnormalities is of great clinical interest as a potential tool for the combined evaluation of coronary stenosis and its hemodynamic significance. We tested the hypothesis that quantitative 3-dimensional (3D) analysis of myocardial perfusion from MDCT images obtained during regadenoson stress would more accurately detect the presence of significant coronary artery disease (CAD) than identical analysis when performed on resting MDCT images. Methods: We prospectively studied 50 consecutive patients referred for CT coronary angiography (CTCA) who agreed to undergo additional imaging with regadenoson (0.4 mg; Astellas). Images were acquired using prospective gating (256-channel; Philips). Custom analysis software was used to define 3D myocardial segments, and calculate for each segment an index of severity and extent of perfusion abnormality, Qh, which was compared with perfusion defects predicted by the presence and severity of coronary stenosis on CTCA. Results: Three patients were excluded because of image artifacts. In the remaining 47 patients, CTCA depicted stenosis more than 50% in 23 patients in 37 of 141 coronary arteries. In segments supplied by the obstructed arteries, myocardial attenuation was slightly reduced compared with normally perfused segments at rest (mean [SD], 91 [21] vs 93 [26] Hounsfield units, not significant) and, to a larger extent, at peak stress (102 [21] vs 112 [20] Hounsfield units, P < 0.05). In contrast, index Qh was significantly increased at rest (0.40 [0.48] vs 0.26 [0.41], P < 0.05) and reached a nearly 3-fold difference at peak stress (0.66 [0.74] vs 0.28 [0.51], P < 0.05). The addition of regadenoson improved the diagnosis of CAD, as reflected by an increase in sensitivity (from 0.57 to 0.91) and improvement in accuracy (from 0.65 to 0.77). Conclusions: Quantitative 3D analysis of MDCT images allows objective detection of CAD, the accuracy of which is improved by regadenoson stress.