BACKGROUND: Breast attenuation may impact the diagnostic accuracy of stress myocardial perfusion imaging (MPI) with single-photon emission computed tomography (SPECT). We compared the performance of conventional (C)-SPECT and cadmium-zinc-telluride (CZT)-SPECT systems in women with low-intermediate likelihood of coronary artery disease (CAD). METHODS AND RESULTS: A total of 109 consecutive women underwent stress-optional rest MPI by both C-SPECT and CZT-SPECT. In the overall study population, a weak albeit significant correlation between total perfusion defect (TPD) measured by C-SPECT and CZT-SPECT was observed (r = 0.38, P < .001) and at Bland-Altman analysis the mean difference in TPD (C-SPECT minus CZT-SPECT) was 2.40% (P < .001). Overall concordance of semi-quantitative diagnostic performance between C-SPECT and CZT-SPECT was observed in 52 (48%) women with a kappa value of 0.09. Normalcy rate was significantly higher using CZT-SPECT compared to C-SPECT (P < .001). Machine learning analysis performed through the implementation of J48 algorithm proved that CZT-SPECT has higher sensitivity, specificity, and accuracy than C-SPECT. CONCLUSIONS: In women with low-intermediate likelihood of CAD, there is a poor concordance of diagnostic performance between C-SPECT and CZT-SPECT, and CZT-SPECT allows better normalcy rate detection compared to C-SPECT.