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As incidence of differentiated thyroid cancer rises, treatment paradigms have become increasingly defined. Despite this, locally advanced disease continues to be challenging to manage. Postoperative therapy in the form of radioactive iodine (RAI) is generally recommended, but the role of external beam radiation therapy (EBRT) is less well defined.To investigate the role of EBRT in locally advanced differentiated thyroid cancer.For this retrospective cohort study, patients treated surgically for T4a differentiated thyroid cancer at the University of Texas MD Anderson Cancer Center from January 2000 through December 2015 were recruited, and 88 patients were included for analysis.Adjuvant treatment with RAI alone or both RAI and EBRT.Disease-free survival (DFS), defined as the time from primary surgery to locoregional or distant recurrence or death due to any cause. Kaplan-Meier survival analysis was completed. Univariate and multivariate analysis was completed with Cox proportional hazards model to determine predictors of DFS.A total of 88 patients (44 women [50%]; mean [SD] age, 58.2 [15.3] years) were included in the analysis. Median (range) follow-up was 117 (12-164) months. Forty-four patients (50%) underwent RAI alone and 44 patients (50%) underwent RAI with adjuvant EBRT. Patients undergoing RAI alone did not receive EBRT owing to invasion into the recurrent laryngeal nerve only (n = 14 [32%]) or invasion into the tracheal perichondrium and/or esophageal muscularis only (n = 18 [41%]). Five-year DFS was 43% in those undergoing RAI alone, compared with 57% in those undergoing RAI and EBRT (effect size = 14%; 95% CI, −7% to 33%). Patients undergoing RAI alone had an increased rate of locoregional failure (effect size = −32%; 95% CI, −47% to −16%), with those undergoing RAI treatment alone, for minimal tracheal perichondrium and/or esophageal muscularis invasion having worse locoregional control than those with recurrent laryngeal nerve invasion only (effect size = 49%; 95% CI, 20% to 71%). Age (adjusted hazard ratio [adjusted HR], 1.02/y; 95% CI, 1.00 to 1.05) and esophageal invasion (adjusted HR, 2.30; 95% CI, 1.16 to 4.60) were independent predictors of worse DFS.The addition of EBRT to RAI results in good disease control in locally advanced differentiated thyroid cancer, particularly in patients with tracheal or esophageal invasion treated with aggressive surgical resection. Increased age and presence of esophageal invasion were independent predictors of poor disease control.