Introduction PET myocardial perfusion imaging (MPI) is the standard technique for assessing myocardial function, but provides limited information on the anatomy of cardiac structures whereas the coronary artery calcium (CAC) score provides information on calcified plaque burden and the anatomical structure of the coronary arteries. The aim of this study was to determine the relationship between quantitative myocardial blood flow (MBF), CAC, and coronary artery disease (CAD). This work also aims to determine whether MBF quantification and/or CAC add value to relative MPI, and aid in the reclassification of patients with CAD. This way, a 'gatekeeper' study could be identified to predict coronary artery stenosis and improve our clinical service. Materials and methods Rubidium-82 PET/CT MPI, calcium score, and computed tomographic coronary angiography imaging were performed in 128 patients with known or suspected CAD. The presence of ischemia was assessed from qualitative reporting of rubidium-82 MPI, and using the same data, quantitative values of MBF and coronary flow reserve (CFR) were derived. Calcium score images were quantitatively analyzed and categorized into three groups defined by CAC values of 0,1-400, and > 400. Significant stenosis was classified as stenosis of 50% or more on computed tomographic angiography. Results A total of 120 patients were included in the final analysis (77 men, 43 women). Our results showed an inverse correlation between stress MBF, CFR, and the percentage stenosis as well as an inverse correlation compared with CAC. A direct correlation between CAC and the percentage stenosis was observed, indicating that an increase in coronary calcification in individual coronary arteries is related to the severity of the coronary stenosis. These results proved that the addition of stress MBF to relative MPI (32%) resulted in a significantly higher sensitivity (48%, P=0.002), which increased significantly more with the addition of CFR (58%, P≤0.001). The further addition of CAC resulted in a significantly higher sensitivity (80%, P =0.001), with an even higher sensitivity with the addition of both CFR and CAC (95%, P ≤0.001) to relative MPI. Conclusion The addition of quantitative MBF conferred a substantial added diagnostic value to relative MPI for the diagnosis of CAD by highlighting compromised flow with the addition of CAC, increasing this added value even more. We recommend that this approach should be used to predict the presence of coronary artery stenosis at its earliest stage and guide physicians when making decisions on the management pathway of CAD without exposing patients to a high radiation dose during cardiac angiography.