ABSTRACT: Background Quantitative flow ratio ( QFR ) has a high diagnostic accuracy in assessing functional stenoses relevance, as judged by fractional flow reserve ( FFR ). However, its diagnostic performance has not been thoroughly evaluated using instantaneous wave-free ratio ( iFR ) or coronary flow reserve as the reference standard. This study sought to evaluate the diagnostic performance of QFR using other reference standards beyond FFR . Methods and Results We analyzed 182 patients (253 vessels) with stable ischemic heart disease and 82 patients (105 nonculprit vessels) with acute myocardial infarction in whom coronary stenoses were assessed with FFR , iFR, and coronary flow reserve. Contrast QFR analysis of interrogated vessels was performed in blinded fashion by a core laboratory, and its diagnostic performance was evaluated with respect to the other invasive physiological indices. Mean percentage diameter stenosis, FFR , iFR , coronary flow reserve, and QFR were 53.1±19.0%, 0.80±0.13, 0.88±0.12, 3.14±1.30, and 0.81±0.14, respectively. QFR showed higher correlation ( r=0.863 with FFR versus 0.740 with iFR , P<0.001), diagnostic accuracy (90.8% versus 81.3%, P<0.001), and discriminant function (area under the curve=0.953 versus 0.880, P<0.001) when FFR was used as a reference standard than when iFR was used as the reference standard. However, when coronary flow reserve was used as an independent reference standard, FFR , iFR , and QFR showed modest discriminant function (area under the curve=0.682, 0.765, and 0.677, respectively) and there were no significant differences in diagnostic accuracy among FFR , iFR , and QFR (65.4%, 70.6%, and 64.9%; all P values in pairwise comparisons >0.05, overall comparison P=0.061). Conclusions QFR has a high correlation and agreement with respect to both FFR and iFR , although it is better when FFR is used as the comparator. As a pressure-derived index not depending on wire or adenosine, QFR might be a promising tool for improving the adoption rate of physiology-based revascularization in clinical practice.