BACKGROUND. Estimation of fractional flow reserve from coronary CTA (FFR-CT) is an established method of assessing the hemodynamic significance of coronary lesions. However, clinical implementation has progressed slowly, partly because of off-site data transfer with long turnaround times for results. OBJECTIVE. The purpose of this study was to evaluate the diagnostic performance of FFR-CT computed on-site with a high-speed deep learning-based algorithm with invasive hemodynamic indexes as the reference standard. METHODS. This retrospective study included 59 patients (46 men, 13 women; mean age, 66.5 ± 10.2 years) who underwent coronary CTA (including calcium scoring) followed within 90 days by invasive angiography with invasive fractional flow reserve (FFR) and/or instantaneous wave-free ratio measurements from December 2014 to October 2021. Coronary artery lesions were considered to have hemodynamically significant stenosis in the presence of invasive FFR of 0.80 or less and/or instantaneous wave-free ratio of 0.89 or less. A single cardiologist evaluated the CTA images using an on-site deep learning-based semiautomated algorithm entailing a 3D computational flow dynamics model to determine FFR-CT for coronary artery lesions detected with invasive angiography. Time for FFR-CT analysis was recorded. FFR-CT analysis was repeated by the same cardiologist in 26 randomly selected examinations and by a different cardiologist in 45 randomly selected examinations. Diagnostic performance and agreement were assessed. RESULTS. A total of 74 lesions were identified with invasive angiography. FFR-CT and invasive FFR had strong correlation (r = 0.81) and, in Bland-Altman analysis, bias of 0.01 and 95% limits of agreement of -0.13 to 0.15. FFR-CT had AUC for hemodynamically significant stenosis of 0.975. At a cutoff of 0.80 or less, FFR-CT had 95.9% accuracy, 93.5% sensitivity, and 97.7% specificity. In 39 lesions with severe calcifications (≥ 400 Agatston units), FFR-CT had AUC of 0.991 and at a cutoff of 0.80, 94.7% sensitivity, 95.0% specificity, and 94.9% accuracy. Mean analysis time per patient was 7 minutes 54 seconds. Intraobserver agreement (intraclass correlation coefficient, 0.85; bias, -0.01; 95% limits of agreement, -0.12 and 0.10) and interobserver agreement (intraclass correlation coefficient, 0.94; bias, -0.01; 95% limits of agreement, -0.08 and 0.07) were good to excellent. CONCLUSION. A high-speed on-site deep learning-based FFR-CT algorithm had excellent diagnostic performance for hemodynamically significant stenosis with high reproducibility. CLINICAL IMPACT. The algorithm should facilitate implementation of FFR-CT technology into routine clinical practice.