We assessed optimal intravascular ultrasound (IVUS) criteria for predicting functional significance of intermediate coronary lesions. Overall, 201 patients with 236 coronary lesions underwent IVUS and invasive physiological assessment before intervention. Fractional flow reserve (FFR) was measured at maximal hyperemia induced by intravenous adenosine infusion. FFR <0.80 at maximum hyperemia was seen in 49 (21%) of the overall 236 lesions. The independent determinants of FFR were minimal lumen area (MLA; β=0.020; 95% confidence interval [CI], 0.008 to 0.031; P=0.032), plaque burden (β=-0.002; 95% CI, -0.003 to 0.001; P=0.001), lesion length with a lumen area <3.0 mm(2) (β=-0.003; 95% CI, -0.005 to -0.001; P=0.005), and left anterior descending artery location (β=-0.035; 95% CI, -0.055 to -0.016; P=0.001). The best cutoff value (with a maximal accuracy) of the MLA to predict FFR <0.80 was <2.4 mm(2), with a diagnostic accuracy of 68% (90% sensitivity, 60% specificity, and area under the curve=0.800; 95% CI, 0.742 to 0.848; P<0.001). The cutoff value of plaque burden to predict FFR <0.80 was ≥79% (69% sensitivity, 72% specificity, and area under the curve=0.756; 95% CI, 0.696 to 0.810; P<0.001). The cutoff value of lesion length with a lumen area <3.0 mm(2) was 3.1 mm (84%sensitivity, 63%specificity, and area under the curve=0.765; 95% CI, 0.706 to 0.818; P<0.001). Among 117 lesions with an MLA ≥2.4 mm(2), 112 (96%) had an FFR ≥0.80,; and all but 1 showed FFR ≥0.75. Conversely, 44 (37%) lesions with an MLA <2.4 mm(2) had an FFR <0.80. IVUS-derived MLA ≥2.4 mm(2) may be useful to exclude FFR <0.80, but poor specificity limits its value for physiological assessment of lesions with MLA <2.4 mm(2). Thus, FFR or stress tests may be necessary to accurately identify ischemia-inducible intermediate stenoses.