Abstract Background Atherosclerotic plaque quantification from coronary computed tomography angiography (CTA) enables accurate assessment of coronary artery disease burden, progression, and prognosis. However, quantitative plaque analysis is time-consuming and requires high expertise. We sought to develop and externally validate an artificial intelligence (AI)-based deep learning (DL) approach for CTA-derived measures of plaque volume and stenosis severity. We compared the performance of DL to expert readers and the gold standard of intravascular ultrasound (IVUS). Methods This was a multicenter study of patients undergoing coronary CTA at 11 sites, with software-based quantitative plaque measurements performed at a per-lesion level by expert readers. AI-based plaque analysis was performed by a DL novel convolutional neural network which automatically segmented the coronary artery wall, lumen, and plaque for the computation of plaque volume and stenosis severity. Using expert measurements as ground truth, the DL algorithm was trained on 887 patients (4,686 lesions). Thereafter, the algorithm was applied to an independent test set of 221 patients (1,234 lesions), which included an external validation cohort of 171 patients from the SCOT-HEART (Scottish Computed Tomography of the Heart) trial as well as 50 patients who underwent IVUS within one month of CTA. We report the performance of AI-based plaque analysis in the independent test set. Results Within the external validation cohort, there was excellent agreement between DL and expert reader measurements of total plaque volume (intraclass correlation coefficient [ICC] 0.876), noncalcified plaque volume (ICC 0.869), and percent diameter stenosis (ICC 0.850; all p<0.001). When compared with IVUS, there was excellent agreement for DL total plaque volume (ICC 0.945), total plaque burden (ICC 0.853), minimal luminal area (ICC 0.864), and percent area stenosis (ICC 0.805; all p<0.001); with strong correlation between DL and IVUS for total plaque volume (r=0.915; p<0.001; Figure). The average DL plaque analysis time was 20 seconds per patient, compared with 25–30 minutes taken by experts. Conclusions AI-based plaque quantification from coronary CTA using an externally validated DL approach enables rapid measurements of plaque volume and stenosis severity in close agreement with expert readers and IVUS. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Heart, Lung, and Blood Institute, United States