Aims Hybrid myocardial perfusion imaging with single photon emission computed tomography (SPECT) and CT coronary angiography (CCTA) has the potential to play a major role in patients with non-conclusive SPECT or CCTA results. We evaluated the performance of hybrid SPECT/CCTA vs. standalone SPECT and CCTA for the diagnosis of significant coronary artery disease (CAD) in patients with an intermediate to high pre-test likelihood of CAD. Methods In total, 98 patients (mean age 62.5 +/- 10.1 years, 68.4% male) with stable anginal complaints and a median pre-test and results likelihood of 87% (range 22-95%) were prospectively included in this study. Hybrid SPECT/CCTA was performed prior to conventional coronary angiography (CA) including fractional flow reserve (FFR) measurements. Hybrid analysis was performed by combined interpretation of SPECT and CCTA images. The sensitivity, specificity, positive (PPV), and negative (NPV) pred Conclusions In > 40% of the patients with a high pre-test likelihood no significant CAD was demonstrated, emphasizing the value of accurate pre-treatment cardiovascular imaging. Hybrid SPECT/CCTA was able to accurately diagnose and exclude significant CAD surpassing standalone myocardial SPECT and CCTA, vs. a reference standard of FFR measurements.