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Background: Barrett's esophagus (BE) is a diagnosis of esophageal intestinal metaplasia, which can progress to esophageal adenocarcinoma (EAC), and guidelines recommend endoscopic surveillance for early detection and treatment of EAC. However, current practices have limited effectiveness in risk-stratifying patients with BE., Aim: This study aimed to evaluate use of the TSP-9 test in risk-stratifying clinically relevant subsets of patients with BE in clinical practice., Methods: TSP-9 results for tests ordered by 891 physicians for 8080 patients with BE with clinicopathologic data were evaluated. Orders were from nonacademic (94.3%) and academic (5.7%) settings for nondysplastic BE (NDBE; n=7586; 93.9%), indefinite for dysplasia (IND, n=312, 3.9%), and low-grade dysplasia (LGD, n=182, 2.3%)., Results: The TSP-9 test scored 83.2% of patients with low risk, 10.6% intermediate risk, and 6.2% high risk, respectively, for progression to HGD/EAC within 5 years. TSP-9 provided significant risk-stratification independently of clinicopathologic features, within NDBE, IND, and LGD subsets, male and female, and short- and long-segment subsets of patients. TSP-9 identified 15.3% of patients with NDBE as intermediate/high-risk for progression, which was 6.4 times more than patients with a pathology diagnosis of LGD. Patients with NDBE who scored intermediate or high risk had a predicted 5-year progression risk of 8.1% and 15.3%, respectively, which are similar to and higher than published progression rates in patients with BE with confirmed LGD., Conclusions: The TSP-9 test identified a high-risk subset of patients with NDBE who were predicted to progress at a higher rate than confirmed LGD, enabling early detection of patients requiring management escalation to reduce the incidence of EAC. TSP-9 scored the majority of patients with NDBE as low risk, providing support to adhere to 3- to 5-year surveillance per guidelines., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)