BACKGROUND: Positron Emission Tomography (PET) myocardial perfusion imaging (MPI) is a powerful tool for predicting coronary artery disease (CAD). Coronary artery calcium (CAC) provides incremental risk stratification to PET-MPI and enhances diagnostic accuracy. We assessed additive value of CAC score, derived from PET/CT attenuation maps to stress TPD results using the novel 18F-flurpiridaz tracer in detecting significant CAD. METHODS AND RESULTS: Patients from F-flurpiridaz phase III clinical trial who underwent PET/CT MPI with F-flurpiridaz tracer, had available CT attenuation correction (CTAC) scans for CAC scoring, and underwent invasive coronary angiography (ICA) within a 6-month period between 2011 and 2013, were included. Total perfusion deficit (TPD) was quantified automatically, and CAC scores from CTAC scans were assessed using artificial intelligence (AI)-derived segmentation and manual scoring. Obstructive CAD was defined as ≥50% stenosis in Left Main (LM) artery, or 70% or more stenosis in any of the other major epicardial vessels. Prediction performance for CAD was assessed by comparing the area under receiver operating characteristic curve (AUC) for stress TPD alone and in combination with CAC score. Among 498 patients (72% males, median age 63 years) 30.1% had CAD. Incorporating CAC score resulted in a greater AUC: manual scoring (AUC=0.87, 95% Confidence Interval [CI] 0.34-0.90; p=0.015) and AI-based scoring (AUC=0.88, 95%CI 0.85-0.90; p=0.002) compared to stress TPD alone (AUC 0.84, 95% CI 0.80-0.92). CONCLUSIONS: Combining automatically derived TPD and CAC score enhances F-flurpiridaz PET MPI accuracy in detecting significant CAD, offering a method that can be routinely used with PET/CT scanners without additional scanning or technologist time. CONDENSED ABSTRACT: We assessed the added value of CAC score from hybrid PET/CT CTAC scans combined with stress TPD for detecting significant CAD using novel F-flurpiridaz tracer Patients from the F-flurpiridaz phase III clinical trial (n=498, 72% male, median age 63) who underwent PET/CT MPI and ICA within 6-months were included. TPD was quantified automatically, and CAC scores were assessed by AI and manual methods. Adding CAC score to TPD improved AUC for manual (0.87) and AI-based (0.88) scoring versus TPD alone (0.84). Combining TPD and CAC score enhances F-flurpiridaz PET MPI accuracy for CAD detection.