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Objective: Detection of residual differentiated thyroid cancer is important but difficult. A variety of imaging modalities and biochemical markers has been used with moderately good success. We hypothesized that elevated perioperative serum antithyroglobulin antibody (TgAb) levels would also be a predictive marker for persistent or recurrent thyroid cancer., Methods: We performed a retrospective analysis of 277 differentiated thyroid cancer survivors divided into 2 groups: (1) those with low or normal serum TgAb (TgAb-) and (2) those with elevated serum TgAb (TgAb+). All patients were seen at one major academic medical center. Patients were followed for a median of 7.54 years., Results: Patients in the TgAb+ group were more likely to have positive lymph nodes at initial surgery, to be assigned to a higher American Joint Committee on Cancer stage, and to have significantly higher incidence of persistent/recurrent disease. The higher incidence of persistent/recurrent cancer was significant under univariable and multivariable (including TgAb status, age, and sex) Cox proportional hazards model analysis., Conclusion: We conclude that individuals with elevated serum TgAb at the outset should be followed with a higher index of suspicion for persistent/recurrent thyroid cancer., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)