Background: This study aimed to investigate the diagnostic value of comprehensive on-site coronary computed tomography angiography (CCTA) using stenosis and plaque measures and subtended myocardial mass (V sub) for fractional flow reserve (FFR) defined hemodynamically obstructive coronary artery disease (CAD). Additionally, the incremental diagnostic value of off-site CT-derived FFR (FFR CT) was assessed. Methods: Prospectively enrolled patients underwent CCTA followed by invasive FFR interrogation of all major coronary arteries. Vessels with ≥30% stenosis were included for analysis. On-site CCTA assessment included qualitative and quantitative stenosis (visual grading and minimal lumen area, MLA) and plaque measures (characteristics and volumes), and V sub. Diagnostic value of comprehensive on-site CCTA assessment was tested by comparing area under the curves (AUC). In vessels with available FFR CT, the incremental value of off-site FFR CT was tested. Results: In 236 vessels (132 patients), MLA, positive remodeling, non-calcified plaque volume, and V sub were independent on-site CCTA predictors for hemodynamically obstructive CAD (p < 0.05 for all). V sub/MLA 2 outperformed all these on-site CCTA parameters (AUC = 0.85) and V sub was incremental to all other CCTA predictors (p = 0.02). In subgroup analysis (n = 194 vessels), diagnostic performance of FFR CT and V sub/MLA 2 was similar (AUC 0.89 and 0.85 respectively, p = 0.25). Furthermore, diagnostic performance significantly albeit minimally increased when FFR CT was added to on-site CCTA assessment (ΔAUC = 0.03, p = 0.02). Conclusions: In comprehensive on-site CCTA assessment, V sub/MLA2 demonstrated greatest diagnostic value for hemodynamically obstructive CAD and V sub was incremental to all evaluated CCTA indices. Additionally, adding FFR CT only minimally increased diagnostic performance, demonstrating that on-site CCTA assessment is a reasonable alternative to FFR CT. Several novel indices have been proposed to increase the diagnostic performance of coronary computed tomography angiography (CCTA). The diagnostic value of comprehensive on-site CCTA assessment using qualitative and quantitative stenosis and plaque measures and subtended myocardial mass (V sub) for fractional flow reserve (FFR) defined hemodynamically obstructive CAD was assessed in 236 vessels with ≥30% stenosis (132 patients). V sub/MLA 2 demonstrated greatest diagnostic value and V sub was incremental to all evaluated CCTA indices. The addition of off-site CT-derived FFR (FFR CT, in 192 vessels) only minimally increased diagnostic performance, demonstrating that on-site CCTA assessment is a reasonable alternative to off-site assessment using FFR CT.