Abstract Background A new model of computational fluid dynamics (CFD)-based algorithm for coronary CT angiography (CCTA)-derived fractional flow reserve (FFR) (CT-FFR) analysis by expanding the coronary tree to smaller-diameter lumen (0.8mm) using Newton–Krylov–Schwarz (NKS) method to solve the three-dimensional time-dependent incompressible Navier-Stokes equations has been developed; however, the diagnostic performance of this new method has not been sufficiently investigated. Objectives The aim of this study was to determine the diagnostic performance of a novel CT-FFR technique by expanding the coronary tree in the CFD domain. Methods Six centers enrolled 338 symptomatic patients with suspected or known coronary artery disease (CAD) who were prospectively underwent CCTA and FFR. Stenosis assessment in CCTA and CT-FFR analysis were performed in independent core laboratories. Hemodynamically significant stenosis was defined by an CT-FFR and FFR ≤0.80, and anatomically obstructive CAD was defined as a CCTA with stenosis ≥50%. Diagnostic performance of CT-FFR was evaluated against invasive FFR using receiver operator characteristic (ROC) curve analysis. The correlation between CT-FFR and invasive FFR was analyzed using the Spearman correlation coefficient and Bland-Altman analysis. Intra-observer and inter-observer agreement were evaluated utilizing the intraclass correlation coefficient (ICC). Results In this study, 338 patients with 422 targeted vessels were investigated, revealing hemodynamically significant stenosis in 31.1% (105/338) of patients and anatomically obstructive stenosis in 54.1% of patients. On a per-vessel basis, the area under the receiver-operating characteristic curve for CT-FFR was 0.94 versus 0.76 for CCTA (p < 0.001). Per-vessel accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 89.8%, 89.3%, 90.0%, 79.0%, and 99.2%, respectively, for CT-FFR and were 68.4%, 82.8%, 62.3%, 48.1%, and 89.6%, respectively, for CCTA stenosis. CT-FFR and FFR were well correlated (r = 0.775, p < 0.001) with a Bland-Altman bias of 0.0011, and limits of agreement from -0.1509 to 0.1531 (p = 0.770). The intraclass correlation coefficients with CT-FFR for intro- and inter-observer agreement were 0.919 (95% CI: 0.866 to 0.952) and 0.909 (95% CI: 0.851 to 0.945), respectively. The average computation time for CT-FFR analysis was maintained at 11.7 minutes. Conclusion This novel CT-FFR model with the inclusion of smaller lumen provides high diagnostic accuracy in detecting hemodynamically significant CAD. Furthermore, the integration of the NKS method ensures that the computation time remains within an acceptable range for potential clinical applications in the future.