To assess the diagnostic performance of fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) (CT-FFR) obtained by a new computational fluid dynamics (CFD) algorithm to detect ischemia, using FFR as a reference, and analyze the characteristics of "gray zone" and misdiagnosed lesions. This prospective multicenter clinical trial (NCT03692936, https://clinicaltrials.gov/) analyzed 317 patients with coronary stenosis between 30 and 90% in 366 vessels from five centers undergoing CTA and FFR between November 2018 and March 2020. CT-FFR were obtained from a CFD algorithm (Heartcentury Co., Ltd., Beijing, China). Diagnostic performance of CT-FFR and CTA in detecting ischemia was assessed. Coronary atherosclerosis characteristics of gray zone and misdiagnosed lesions were analyzed. Per-vessel sensitivity, specificity and accuracy for CT-FFR and CTA were 89.9, 87.8, 88.8% and 89.3, 35.5, 60.4%, respectively. Accuracy of CT-FFR was 80.0% in gray zone lesions. In gray zone lesions, lumen area and diameter were significantly larger than lesions with FFR < 0.76 (both p < 0.001), lesion length, non-calcified and calcified plaque volume were all significantly higher than non-ischemic lesions (all p < 0.05). In gray zone lesions, Agatston score (OR = 1.009, p = 0.044) was the risk factor of false negative results of CT-FFR. In non-ischemia lesions, coronary stenosis >50% (OR = 2.684, p = 0.03) was the risk factor of false positive results. Lumen area (OR = 0.567, p = 0.02) and diameter (OR = 0.296, p = 0.03) had a significant negative effect on the risk of false positive results of CT-FFR. In conclusion, CT-FFR based on the new parameter-optimized CFD model provides better diagnostic performance for lesion-specific ischemia than CTA. For gray zone lesions, stenosis degree was less than those with FFR < 0.76, and plaque load was heavier than non-ischemic lesions.