Objectives The current study evaluates the incremental value of transluminal attenuation gradient (TAG), TAG with corrected contrast opacification (CCO), and TAG with exclusion of calcified coronary segments (ExC) over coronary computed tomography angiogram (CTA) alone using fractional flow reserve (FFR) as the gold standard. Background TAG is defined as the contrast opacification gradient along the length of a coronary artery on a coronary CTA. Preliminary data suggest that TAG provides additional functional information. Interpretation of TAG is hampered by multiple heartbeat acquisition algorithms and coronary calcifications. Two correction models have been proposed based on either dephasing of contrast delivery by relating coronary density to corresponding descending aortic opacification (TAG-CCO) or excluding calcified coronary segments (TAG-ExC). Methods Eighty-five patients with intermediate probability of coronary artery disease were prospectively included. All patients underwent step-and-shoot 256-slice coronary CTA. TAG, TAG-CCO, and TAG-ExC analyses were performed followed by invasive coronary angiography in conjunction with FFR measurements of all major coronary branches. Results Thirty-four patients (40%) were diagnosed with hemodynamically-significant coronary artery disease (i.e., FFR ≤0.80). On a per-vessel basis (n = 253), 59 lesions (23%) were graded as hemodynamically significant, and the diagnostic accuracy of coronary CTA (diameter stenosis ≥50%) was 95%, 75%, 98%, and 54% for sensitivity, specificity, negative predictive value, and positive predictive value, respectively. TAG and TAG-ExC did not discriminate between vessels with or without hemodynamically significant lesions (-13.5 ;plusmn& 17.1 HU [Hounsfield units] ;times&10 mm;bsupesup&vs. -11.6 ;plusmn&13.3 HU ;times&10 mm;bsupesup&, p = 0.36; and 13.1 ;plusmn&15.9 HU ;times&10 mm;bsupesup&vs. -11.4 ;plusmn&11.7 HU ;times&10 mm;bsupesup&, p = 0.77, respectively). TAG-CCO was lower in vessels with a hemodynamically-significant lesion (-0.050 ;plusmn&0.051 10 mm;bsupesup&vs. -0.036 ;plusmn&0.034 10 mm;bsupesup&, p = 0.03) and TAG-ExC resulted in a slight improvement of the net reclassification index (0.021, p ≤ 0.05). Conclusions TAG did not provide incremental diagnostic value over 256-slice coronary CTA alone in assessing the hemodynamic consequences of a coronary stenosis. Correction for temporal nonuniformity of contrast delivery or exclusion of calcified coronary segments slightly enhanced the results. © 2014 by the American College of Cardiology Foundation.