A novel three-dimensional (3D) iterative image reconstruction method (3D-OSEM) has been developed that in phantom studies yielded comparable image quality at one half the imaging time. In this study, we compared standard (STD) and rapid (nSPEED) protocols for diagnostic quality of images and quantitation of end-diastolic volume (EDV), end-systolic volume (ESV), left ventricular ejection fraction (LVEF), and perfusion defect severity. At 11 US community centers, 448 patients prospectively underwent rest–stress-gated SPECT imaging using Tc-99m-labeled agent. The difference in quality and diagnostic equivalence of STD and nSPEED images were blindly evaluated by three experts. Defect intensity was quantitated as %normal in the three coronary artery territories. Studies were abnormal in 40% of patients. In 98.7% of stress and 98% of rest images, the nSPEED image quality was identical to or better than the STD images. nSPEED images were diagnostically equivalent to the STD in 444/448 (99%) patients. A high correlation was observed between nSPEED and STD studies for measurement of EDV (Y = 0.957X, R 2 = 0.99), ESV (Y = 0.962X, R 2 = 0.99), and LVEF (Y = 1.005X, R 2 = 0.96). STD and nSPEED studies were not significantly different (P = ns) for quantitative perfusion defect severity. Rapid, gated rest–stress myocardial perfusion upright SPECT imaging may be achieved without compromising perfusion and function information.