To confirm that shortened acquisition time or reduced-activity dose in single-photon emission computed tomography (SPECT) myocardial perfusion imaging reconstructed with Astonish software (AS) does not compromise image quality or diagnostic accuracy. One hundred patients referred for SPECT myocardial perfusion imaging were prospectively studied. The patients were randomly selected to receive the full-dose protocol (group A, n = 54) or the half-dose protocol (group B, n = 46). The patients of group A underwent a 2-day stress/rest protocol. After half-time acquisition, they underwent a full-time acquisition for stress and rest SPECT. Group B underwent a 1-day stress/rest protocol. During peak stress, all patients received an intravenous injection of (99m)Tc-methoxyisobutylisonitrile (MIBI; 5.2 ± 0.6 mCi). After the full-time stress acquisition, the patients underwent a double-time stress acquisition. If the stress image showed a defect, a patient received (99m)Tc-MIBI (19.5 ± 1.7 mCi) at rest on the same day. The rest SPECT acquisition protocol was the same in both groups. The low count (LC) and high count (HC) were acquired for each patient. AS and filtered back projection (FBP) reconstructed each set of raw data. Image quality of perfusion was assessed on a four-point scale. Perfusion parameters and function parameters were calculated by quantitative perfusion SPECT and quantitative gated SPECT. Mean image quality for LC-AS and HC-AS (3.5 ± 0.5 and 3.7 ± 0.5, respectively) was superior to HC-FBP (3.1 ± 0.4) in group A (for all, p < 0.001). LC-AS and HC-AS (3.5 ± 0.5 and 3.6 ± 0.5, respectively) in group B were superior to HC-FBP (3.1 ± 0.3) (for all, p < 0.001). LC-AS, HC-AS and LC-FBP showed high diagnostic concordance with HC-FBP (kappa value was 0.92, 0.92, and 0.94, respectively; all p < 0.001). Cardiac SPECT studies can be acquired with half of the scan time or reduced radioactivity dose and reconstructed by using the AS algorithm without compromising image quality.