Abstract Aims Clinical likelihood (CL) models are designed based on a reference of coronary stenosis in patients with suspected obstructive coronary artery disease. However, a reference standard for myocardial perfusion defects (MPDs) could be more appropriate. We aimed to investigate the ability of the 2019 European Society of Cardiology pre-test probability (ESC-PTP), the risk-factor-weighted (RF-CL) model, and coronary artery calcium score-weighted (CACS-CL) model to diagnose MPDs. Methods and results Symptomatic stable de novo chest pain patients (n = 3374) underwent coronary computed tomography angiography and subsequent myocardial perfusion imaging by single-photon emission computed tomography, positron emission tomography, or cardiac magnetic resonance. For all modalities, MPD was defined as coronary computed tomography angiography with suspected stenosis and stress-perfusion abnormality in ≥2 segments. The ESC-PTP was calculated based on age, sex, and symptom typicality, and the RF-CL and CACS-CL additionally included a number of risk factors and CACS. In total, 219/3374 (6.5%) patients had an MPD. Both the RF-CL and the CACS-CL classified substantially more patients to low CL (<5%) of obstructive coronary artery disease compared with the ESC-PTP (32.5 and 54.1 vs. 12.0%, P < 0.001) with preserved low prevalences of MPD (<2% for all models). Compared with the ESC-PTP [area under the receiver-operating characteristic curve (AUC) 0.74 (0.71–0.78)], the discrimination of having an MPD was higher for the CACS-CL model [AUC 0.88 (0.86–0.91), P < 0.001], while it was similar for the RF-CL model [AUC 0.73 (0.70–0.76), P = 0.32]. Conclusion Compared with basic CL models, the RF-CL and CACS-CL models improve down classification of patients to a very low-risk group with a low prevalence of MPD.