Although quantitative coronary angiography (QCA) has been used to determine lesion severity, angiographically derived parameters of translesional physiology have not been compared with those directly measured in the same patients. Thus, the aim of this study was to correlate QCA-derived translesional pressure and flow data with directly measured data in patients. QCA (DCI-ACA program), translesional pressure gradient (2.2Fr fluid-filled tracking catheter), and intracoronary Doppler flow velocity (0.018-inch FloWire ™ measurements were simultaneously performed in 28 arteries (25 patients). Mean diameter stenosis was 51 ± 2.3% (range 29 to 73). No patient had left ventricular hypertrophy or valvular heart disease. The arteries studied were left anterior descending in 14, circumflex in 8, and right coronary in 6 patients. Stenotic flow reserve and baseline and maximal gradients were calculated by the DCI program. Coronary flow reserve and baseline and maximal hyperemic gradients were also directly measured distal to the stenosis after administration of intracoronary adenosine (12 to 18 μg). QCA-derived pressure gradients did not correlate with the measured gradients at baseline (r2 = 0.005; p = 0.73) or at maximal hyperemia (r2 = 0.1; p = 0.13). No correlation was found between the QCA-predicted flow reserve and the coronary flow reserve measured distal to the stenosis (r2 = 0.02; p = 0.46). Furthermore, stenotic flow reserve and measured gradient were not significantly correlated (r2 = 0.1; p = 0.16). In this range of stenoses of intermediate severity, there was no correlation between the measured pressure gradient or coronary flow reserve and lesion diameter or cross-sectional area by QCA. These results indicate that due to inherent limitations of angiography and theoretical assumptions of the physiologic state, QCA-derived parameters of translesional physiology, particularly relevant for intermediately severe lesions, do not correlate with directly measured pressure and flow beyond the stenosis. Given these limitations, caution should be applied in utilizing these parameters for clinical decision-making. QCA-derived parameters may benefit from further refinement in determining the hemodynamic significance of coronary stenoses.