Objectives This study sought to determine the diagnostic performance of noninvasive fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) (FFR _CT ) for the diagnosis of lesion-specific ischemia in nonculprit vessels of patients with recent in ST-segment elevation myocardial infarction (STEMI). Background In patients with stable angina, FFR _CT has high diagnostic performance in identification of ischemia-causing lesions. The potential value of FFR _CT for assessment of multivessel disease in patients with recent STEMI has not been evaluated. Methods Coronary CTA with calculation of FFR _CT and invasive coronary angiography with FFR were performed 1 month after STEMI in patients with multivessel disease. Coronary CTA and invasive coronary angiography stenosis >50% were considered obstructive. Lesion-specific ischemia was assumed if FFR _CT was ≤0.80. FFR ≤0.80 was the reference standard. To evaluate the influence of vessel size, the total coronary vessel lumen volume relative to left ventricular mass (volume-to-mass ratio) was calculated and compared with that of patients with stable angina. Results The study evaluated 124 nonculprit vessels from 60 patients. Accuracy, sensitivity, and specificity of FFR _CT were 72%, 83%, and 66% versus 64% (p = 0.033), 93% (p = 0.15), and 49% (p < 0.001) for CTA and 72% (p = 1.00), 76% (p = 0.46), and 70% (p = 0.54) for invasive coronary angiography. Following STEMI, median volume-to-mass ratio was lower than in patients with stable angina, 53 versus 65 mm ³ /g (p = 0.009). In patients with volume-to-mass ratio ≥65 mm ³ /g (upper tertile) accuracy, sensitivity, and specificity of FFR _CT were all 83% versus 56% (p = 0.009), 75% (p = 0.61), and 44% (p = 0.003) in patients with <49 mm ³ /g (lower tertile). Conclusions The diagnostic performance of FFR _CT for staged detection of ischemia in STEMI patients with multivessel disease is moderate. STEMI patients have a smaller vessel volume than do patients with stable angina. The diagnostic performance of FFR _CT is influenced by the volume-to-mass ratio. This study does not support routine use of FFR _CT in the post-STEMI setting. (Assessment of Coronary Stenoses Using Coronary CT-Angiography and Noninvasive Fractional Flow Reserve; NCT01739075)