Background Identification of large vessel occlusion (LVO) is critical to the management of acute ischemic stroke and prerequisite to endovascular therapy in recent trials. Increasing volumes and data complexity compel the development of fast, reliable, and automated tools for LVO detection to facilitate acute imaging triage. Purpose To investigate the performance of an anterior circulation LVO detection platform in a large mixed sample of individuals with and without LVO at cerebrovascular CT angiography (CTA). Materials and Methods In this retrospective analysis, CTA data from recent cerebrovascular trials (CRISP [ClinicalTrials.gov NCT01622517] and DASH) were enriched with local repositories from 11 worldwide sites to balance demographic and technical variables in LVO-positive and LVO-negative examinations. CTA findings were reviewed independently by two neuroradiologists from different institutions for intracranial internal carotid artery (ICA) or middle cerebral artery (MCA) M1 LVO; these observers were blinded to all clinical variables and outcomes. An automated analysis platform was developed and tested for prediction of LVO presence and location relative to reader consensus. Discordance between readers with respect to LVO presence or location was adjudicated by a blinded tertiary reader at a third institution. Sensitivity, specificity, and receiver operating characteristics were assessed by an independent statistician, and subgroup analyses were conducted. Prespecified performance thresholds were set at a lower bound of the 95% CI of sensitivity and specificity of 0.8 or greater at mean times to notification of less than 3.5 minutes. Results A total of 217 study participants (mean age, 64 years ± 16 [standard deviation]; 116 men; 109 with positive findings of LVO) were evaluated. Prespecified performance thresholds were exceeded (sensitivity, 105 of 109 [96%; 95% CI: 91, 99]; specificity, 106 of 108 [98%; 95% CI: 94, 100]). Sensitivity and specificity estimates across age, sex, location, and vendor subgroups exceeded 90%. The area under the receiver operating characteristic curve was 99% (95% CI: 97, 100). Mean processing and notification time was 3 minutes 18 seconds. Conclusion The results confirm the feasibility of fast automated high-performance detection of intracranial internal carotid artery and middle cerebral artery M1 occlusions. © RSNA, 2021 See also the editorial by Kloska in this issue.