Although coronary computed tomographic angiography (CCTA) has been a robust diagnostic tool to identify anatomical significance of coronary artery disease (CAD), the utility of CCTA to assess hemodynamic significance of CAD remains unclear. We investigated the diagnostic performance of transluminal attenuation gradient (TAG) and fractional flow reserve derived from CCTA (FFRCT) to predict lesion-specific ischemia by invasive FFR. We identified 103 patients with suspected or known CAD enrolled from the DISCOVER-FLOW and DeFACTO studies who underwent invasive coronary angiography with FFR and high quality ≥64-slice CCTA. Diagnostic performance for predicting abnormal invasive FFR (≤0.80) was assessed for TAG [≤-1.1 HU/mm by the area under the curve (AUC) by receiver-operating characteristic curve analysis (ROC)], FFR(CT) (≤0.80), and CCTA stenosis (≥50%). On a per-vessel analysis (n = 146), 52 vessels (35.6%) had ischemia by invasive FFR. The sensitivity, specificity, positive predictive value and negative predictive value were 53.8, 45.7, 35.4, 64.2% for TAG, 82.7, 74.5, 64.2, 88.6% for FFR(CT), 84.6, 39.4, 43.6, 82.2% for CCTA stenosis, respectively. The AUC by ROC curve analysis for FFR(CT) (0.79) demonstrated greater discrimination of hemodynamic ischemia compared to TAG (0.50, p < 0.0001 vs. FFR(CT)), CCTA stenosis (0.62, p = 0.0004 vs. FFR(CT)) and the combination of the two (0.63, p = 0.004 vs. FFR(CT)). These results remained consistent regardless of the number of CCTA slices. FFR(CT) allows identification of lesion-specific ischemia using invasive FFR as a reference standard with greater diagnostic accuracy than TAG, CCTA stenosis, or the combination of the two.