Outcome was compared in 1,004 patients with differentiated thyroid carcinoma (DTC) who underwent thyroid remnant ablation with 131I (n = 151) or were either treated with thyroid hormone alone (755) or given no postoperative medical therapy (98). Median follow-up time was 18.7 years for patients treated with thyroid hormone alone, 21.3 years for those given no adjunctive medical therapy, and 14.7 years for those treated with thyroid remnant ablation. End points measured were cancer recurrence, development of distant metastases, and death due to thyroid carcinoma. Tumor recurrence was about threefold lower (p < 0.001) and fewer patients developed distant metastases (p < 0.002) after thyroid remnant ablation than after other forms of postoperative treatment, an effect observed only in patients with primary tumors > or = 1.5 cm in diameter. The doses of 131I were stratified into two groups: 29-50 mCi (mean 47 mCi) in 43% and 51-200 mCi (111 mCi) in 57% of patients. Both groups experienced similar recurrence rates (7% and 9%, respectively, p = 0.7). There were fewer cancer deaths after thyroid remnant ablation than after the other treatment strategies (p < 0.001), differences that occurred only in patients aged 40 years or older at the time of initial treatment and with primary tumors > or = 1.5 cm. The variables that influenced cancer recurrence in a Cox proportional hazards model were absence of cervical lymph node metastases (hazards ratio [HR] 0.8), tumor stage (HR 1.8), and treatment of the thyroid remnant (HR 0.9); those that independently affected cancer-specific death rates were age (HR 13.3), recurrence of cancer (16.6), time to treatment (HR 3.5), thyroid remnant ablation (HR 0.5), and tumor stage (HR 2.3). This study suggests that thyroid remnant ablation is effective in reducing recurrence of DTC in patients of all ages and reduces the risk of death from thyroid carcinoma in patients > age 40 at the time of diagnosis. These effects are not apparent in patients with isolated tumors < 1.5 cm that are not metastatic to regional lymph nodes or invading the thyroid capsule. The optimal dose of 131I necessary to achieve this effect remains uncertain.