Objectives FIRST (Fractional Flow Reserve and Intravascular Ultrasound Relationship Study) aimed to determine the optimal minimum lumen area (MLA) by intravascular ultrasound (IVUS) that correlates with fractional flow reserve (FFR) and to assess the correlation between virtual histology IVUS and FFR for intermediate coronary lesions. Background FFR is considered the gold standard for assessing intermediate coronary lesions. Measurements of ≤0.8 are considered clinically significant and indicative of physiological ischemia. Methods FIRST is a multicenter, prospective, international registry of patients with intermediate coronary lesions, defined as 40% to 80% stenosis by angiography. In total, 350 patients (367 lesions) were enrolled at 10 U.S. and European sites. Patients were followed through hospital discharge. Results Overall, an MLA <3.07 mm2 (64.0% sensitivity, 64.9% specificity, area under curve AUC = 0.65) was the best threshold value for identifying FFR <0.8. The accuracy improved when reference vessel–specific analyses were performed. An MLA <2.4 mm2 (AUC = 0.66) was best for reference vessel diameters <3.0 mm, an MLA <2.7 mm2 (AUC = 0.71) for reference vessel diameters of 3.0 to 3.5 mm, and an MLA <3.6 mm2 (AUC = 0.68) for reference vessel diameters >3.5 mm. FFR correlated with plaque burden (r = −0.220, p < 0.001) but not with other plaque morphology. Conclusions Anatomic measurements by IVUS show a moderate correlation with the FFR values. The optimal cutoff for an MLA to FFR <0.8 is vessel dependent. Plaque morphology characteristics do not correlate with FFR. The utility of IVUS MLA as an alternative to FFR to guide intervention in intermediate lesions may be limited in accuracy and should be tested clinically. (Fractional Flow Reserve and Intravascular Ultrasound Relationship Study FIRST; NCT01153555 )