Background: Recently several publications described the diagnostic value of coronary CT angiography (coronary CTA) derived fractional flow reserve (CTA-FFR). For a recently introduced on-site CTA-FFR application, detailed methodology and factors potentially affecting performance have not yet been described. Objective: To provide a methodological background for an on-site CTA-FFR application and evaluate the effect of patient and acquisition characteristics. Methods: The on-site CTA-FFR application utilized a reduced-order hybrid model applying pressure drop models within stenotic regions. In 116 patients and 203 vessels the diagnostic performance of CTA-FFR was investigated using invasive FFR measurements as a reference. The effect of several potentially relevant factors on CTA-FFR was investigated. Results: 90 vessels (44%) had a hemodynamically relevant stenosis according to invasive FFR (threshold <= 0.80). The overall vessel-based sensitivity, specificity and accuracy of CTA-FFR were 88% (CI 95%: 79 -94%), 65% (55-73%) and 75% (69-81%). The specificity was significantly lower in the presence of misalignment artifacts (25%, CI: 6-57%). A non-significant reduction in specificity from 74% (60-85%) to 48% (26-70%) was found for higher coronary artery calcium scores. Left ventricular mass, diabetes mellitus and large vessel size increased the discrepancy between invasive FFR and CTA-FFR values. Conclusions: On-site calculation of CTA-FFR can identify hemodynamically significant CAD with an overall per-vessel accuracy of 75% in comparison to invasive FFR. The diagnostic performance of CTA-FFR is negatively affected by misalignment artifacts. CTA-FFR is potentially affected by left ventricular mass, diabetes mellitus and vessel size. (C) 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.