Objectives To compare the diagnostic power of separately integrating on-site computed tomography (CT)-derived fractional flow reserve (CT-FFR) and static CT stress myocardial perfusion (CTP) with coronary computed tomography angiography (CCTA) in detecting patients with flow-limiting CAD. The flow-limiting stenosis was defined as obstructive (>= 50%) stenosis by invasive coronary angiography (ICA) with a corresponding perfusion deficit on stress single photon emission computed tomography (SPECT/MPI). Methods Forty-eight patients (74 vessels) were enrolled who underwent research-indicated combined CTA-CTP (320-row CT scanner, temporal resolution 137 ms) and SPECT/MPI prior to conventional coronary angiography. CT-FFR was computed on-site using resting CCTA data with dedicated workstation-based software. All five imaging modalities were analyzed in blinded independent core laboratories. Logistic regression and the integrated discrimination improvement (IDI) index were used to evaluate incremental differences in CT-FFR or CTP compared with CCTA alone. Results The prevalence of obstructive CAD defined by combined ICA-SPECT/MPI was 40%. Per-vessel sensitivity and specificity were 95 and 42% for CCTA, 76 and 89% for CCTA + CTP, and 81 and 96% for CCTA + CT-FFR, respectively. The diagnostic performance of CCTA (AUC = 0.82) was improved by combining it with CT-FFR (AUC = 0.92, p = 0.01; IDI = 0.27, p < 0.001) or CTP (AUC = 0.90, p = 0.02; IDI = 0.18, p = 0.003). Conclusion On-site CT-FFR combined with CCTA provides an incremental diagnostic improvement over CCTA alone in identifying patients with flow-limiting CAD defined by ICA + SPECT/MPI, with a comparable diagnostic accuracy for integrated CTP and CCTA.