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Objective: Discrete anterior mediastinal masses most often represent thymoma or lymphoma. Lymphoma treatment is nonsurgical and requires biopsy. Noninvasive thymoma is ideally resected without biopsy, which may potentiate pleural metastases. This study sought to determine if clinical criteria or positron emission tomography/computed tomography could accurately differentiate the 2, guiding a direct surgery versus biopsy decision., Methods: A total of 48 subjects with resectable thymoma and 29 subjects with anterior mediastinal lymphoma treated from 2006 to 2019 were retrospectively examined. All had pretreatment positron emission tomography/computed tomography and appeared resectable (solitary, without clear invasion or metastasis). Reliability of clinical criteria (age and B symptoms) and positron emission tomography/computed tomography maximum standardized uptake value were assessed in differentiating thymoma and lymphoma using Wilcoxon rank-sum test, chi-square test, and logistic regression. Receiver operating characteristic analysis identified the maximum standardized uptake value threshold most associated with thymoma., Results: There was no association between tumor type and age group (P = .183) between those with thymoma versus anterior mediastinal lymphoma. Patients with thymoma were less likely to report B symptoms (P < .001). The median maximum standardized uptake value of thymoma and lymphoma differed dramatically: 4.35 versus 18.00 (P < .001). Maximum standardized uptake value was independently associated with tumor type on multivariable regression. On receiver operating characteristic analysis, lower maximum standardized uptake value was associated with thymoma. Maximum standardized uptake value less than 12.85 was associated with thymoma with 100.00% sensitivity and 88.89% positive predictive value. Maximum standardized uptake value less than 7.50 demonstrated 100.00% positive predictive value for thymoma., Conclusions: Positron emission tomography/computed tomography maximum standardized uptake value of resectable anterior mediastinal masses may help guide a direct surgery versus biopsy decision. Tumors with maximum standardized uptake value less than 7.50 are likely thymoma and thus perhaps appropriately resected without biopsy. Tumors with maximum standardized uptake value greater than 7.50 should be biopsied to rule out lymphoma. Lymphoma is likely with maximum standardized uptake value greater than 12.85., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)