Purpose To evaluate the performance of a new artificial intelligence (AI)-based tool by comparing the quantified stenosis severity at coronary CT angiography (CCTA) with a reference standard derived from invasive quantitative coronary angiography (QCA). Materials and Methods This secondary, post hoc analysis included 120 participants (mean age, 59.7 years ± 10.8 [SD]; 73 [60.8%] men, 47 [39.2%] women) from three large clinical trials (AFFECTS, P3, REFINE) who underwent CCTA and invasive coronary angiography with QCA. Quantitative analysis of coronary stenosis severity at CCTA was performed using an AI-based coronary stenosis quantification (AI-CSQ) software service. Blinded comparison between QCA and AI-CSQ was measured on a per-vessel and per-patient basis. Results The per-vessel AI-CSQ diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 80%, 88%, 86%, 65%, and 94%, respectively, for diameter stenosis (DS) 50% or greater; and 78%, 92%, 91%, 47%, and 98%, respectively, for DS 70% or greater. The areas under the receiver operating characteristic curve (AUCs) to predict DS of 50% or greater and 70% or greater on a per-vessel basis were 0.92 (95% CI: 0.88, 0.95; P < .001) and 0.93 (95% CI: 0.89, 0.97; P < .001), respectively. The AUCs to predict DS of 50% or greater and 70% or greater on a per-patient basis were 0.93 (95% CI: 0.88, 0.97; P < .001) and 0.88 (95% CI: 0.81, 0.94; P < .001), respectively. Conclusion AI-CSQ at CCTA demonstrated a high diagnostic performance compared with QCA both on a per-patient and per-vessel basis, with high sensitivity for stenosis detection. Keywords: CT Angiography, Cardiac, Coronary Arteries Supplemental material is available for this article. Published under a CC BY 4.0 license.