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Background and Aims: Computer-aided detection (CADe) devices have been shown to increase adenoma detection rates and adenomas per colonoscopy compared to standard colonoscopies. Questions remain about whether CADe colonoscopies are mainly increasing the detection of small, nonneoplastic lesions or if they are detecting more pathologically meaningful polyps. In this analysis, we compare the true histology rate (defined as polyps with confirmation of clinically relevant histopathology) of CADe-identified polyps with polyps identified during standard colonoscopies., Methods: Using data from the SKOUT trial, we compared the true histology rate (THR) between CADe and standard colonoscopies. We also conducted a subgroup analysis by patient, procedural, and endoscopist factors. To account for multiple testing of comparisons, we used the false discovery rate., Results: A total of 1423 participants were included (CADe, n = 714; standard, n = 709). Overall, THR was similar between the CADe and standard colonoscopy arms for adenomas, sessile serrated lesions, and large hyperplastic polyps. Higher THR with CADe colonoscopy was observed in some subgroups for adenomas. Endoscopists with 11 to 20 years of experience and procedures occurring after 12 pm had significantly higher adenoma THRs in the CADe cohort. Patients younger than 65 years, male patients, and procedures with a withdrawal time of ≥8 minutes had borderline significance in the CADe device adenoma THR subgroup., Conclusions: CADe colonoscopies may hold the key to improving endoscopic quality measures, provided that the polyps identified by the CADe device are those of clinical relevance. Although the benefit and significance in the CADe group were demonstrated in this analysis, further research is warranted to ensure that the true histology is maintained when applied in real-world applications., Competing Interests: Disclosure The following authors disclosed financial relationships: A. Shaukat: Research funding to her institution for the current article from Iterative Health, Inc and consulting fees from Freenome Inc and Medtronic. D. R. Lichtenstein: Consulting fees from Ambu and Olympus America Inc and research funding to his institution for the current article from and unremunerated participation in an advisory board for Iterative Health, Inc. D. C. Chung: Research funding to his institution for the current article from Iterative Health. C. Seidl: Employee of and holds stock or stock options in Iterative Health. Y. Wang: Employee of and holds stock or stock options in Iterative Health. E. E. Navajas: Employee of and holds stock or stock options in Iterative Health. D. R. Colucci: Employee of and holds stock or stock options in Iterative Health. S. Baxi: Employee of and holds stock or stock options in Iterative Health. W. R. Brugge: Unremunerated participation on an advisory board for Iterative Health, Inc. All other others disclosed no financial relationships. Support for this analysis was provided to A. Shaukat, D. C. Chung and W. R. Brugge by Iterative Health, Inc, Cambridge, Massachusetts, USA., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)