BACKGROUND : Fractional flow reserve derived from computed tomography (FFRct) has shown higher accuracy for detection of significant coronary artery disease (CAD) compared to coronary computed tomography angiography (CCTA). The performance of a combined comprehensive qualitative interpretation of both CCTA and FFRct in patient management is unknown. We aimed to explore the clinical application of this combined approach. METHODS : We retrospectively reviewed cases referred to FFRct testing at our institution over a one-year period. Patients had documentation of whether invasive coronary angiography (ICA) was performed and revascularization were needed. Interpretations and recommendations of the adopted comprehensive approach (C-FFRct), that took into account focal versus diffuse disease, depth of ischemia and myocardium at risk, were compared to those of CCTA (binary > 50% stenosis) alone and FFRct binary approach (FFRct ≤ 0.8). C-FFRct performance was measured against the decision made upon revascularization. RESULTS : A total of 207 cases were referred to FFRct testing, 163 (79%) accepted and 44 (21%) rejected for quality. C-FFRct changed interpretations and recommendations of 39 (24%) and 14 (9%) CCTA and FFRct, respectively. ICA was deferred in 32 (59%) and 13 (32%) cases; whereas ICA referral rate was 7 (6%) and 1 (0.8%) cases, based on CCTA and FFRct, respectively. No major cardiac events were observed during follow up time (median = 6 months). C-FFRct sensitivity, specificity, and accuracy compared to decision upon revascularization were 89%, 79% and 82%. C-FFRct number needed to treat was 4, and 6, compared to CCTA and FFRct, respectively. CONCLUSIONS : FFRct is a feasible tool to improve the diagnostic performance of CCTA in CAD real-world workup. However, qualitative interpretation of the FFRct report combined with CCTA findings may yield more impactful results on patient management. Further prospective studies are warranted to validate the application of this approach and better define its components.