Context: Anti‐thyroglobulin antibodies (anti‐Tg), present in 20%‐25% of differentiated thyroid cancer (DTC) patients, interfere with thyroglobulin measurements posing a challenge in the follow‐up. Objectives: The aim of this study was to identify clinical‐histological factors that may affect anti‐Tg persistence and disease outcome in DTC with positive anti‐Tg. Methods: We retrospectively studied 234 DTC patients, with positive anti‐Tg at diagnosis (females: 82.1%, age at diagnosis: 46.0 ± 14.4 yrs, median follow‐up: 5 yrs (1.5‐32 yrs). 221/234 (94.4%) received radioiodine (RAI) ablation. Patients were divided into two subgroups: those whose anti‐Tg became undetectable (anti‐Tg‐NEG) and those whose anti‐Tg remained positive (anti‐Tg‐POS) at the end of the follow‐up period. Results: Anti‐Tg‐POS patients (n = 80, 34.2%) compared to anti‐Tg‐NEG (n = 154, 65.8%) had more frequently lymph node infiltration (36.3% vs 20.1%, P =.01), extrathyroidal extension (ETE, 35.0% vs 22.1%, P =.04), poorly differentiated DTC and increased tumour size (P ≤.004). They received higher total RAI dose (P <.001). In most cases, additional RAI administration and/or additional surgeries did not lead to anti‐Tg elimination. These had more frequently structural disease persistence/progression compared to anti‐Tg‐NEG (remission: 78.8% vs 95.5%, persistence: 13.8% vs 3.9%, progression: 7.5% vs 0.6%, P <.001). In Kaplan‐Meier analysis, the probability of disease progression was higher in anti‐Tg‐POS. In Cox proportional hazard analysis, the predictors of disease progression were size (P =.002) and ETE (P =.006). Conclusions: Worse histological features are more frequent in patients with anti‐Tg persistence during follow‐up. Further additional RAI administration and/or surgeries do not affect anti‐Tg elimination in most cases. Anti‐Tg persistence correlates with structural persistence although tumour size and extrathyroidal extension are the main predictors of disease progression. [ABSTRACT FROM AUTHOR]