BACKGROUND: Distant metastasis is uncommon in differentiated thyroid cancer and the prognosis is unclear. This study aims to evaluate outcomes and to define independent variables that are associated with tumor-related mortality in patients with distant metastasis from thyroid carcinoma. STUDY DESIGN: A retrospective review of the thyroid cancer research database identified 336 patients with distant metastasis from differentiated thyroid carcinoma treated at a single institution between 1941 and 2000. After excluding patients with local or regional recurrence, distant disease was either the first site of recurrence or was detected at the time of diagnosis of the primary tumor in 242 patients (72%). Patient, tumor, and treatment-related factors were analyzed for their relation to disease-specific survival (DSS) using multivariate Cox regression and the log-rank test. RESULTS: Median survival was 4.1 years and 10-year DSS was 26%. Distant disease was synchronous with the primary diagnosis in 97 of 242 (40%) patients. The site of metastasis was lung only in 103 (43%) patients, bone only in 80 (33%), other sites in 14 (6%), and more than one organ system in 45 (19%). Multivariate analysis identified age 45 years or more, symptoms, site other than lung only or bone only, and no radioactive iodine treatment for the metastasis as predictors of poor outcome with 13%, 11%, 16%, and 12% 10-year DSS, respectively. This compares with age less than 45 years, asymptomatic presentation, metastasis only in the lung or bone, and radioactive iodine treatment with 10-year DSS rates of 58%, 45%, 32%, and 33%, respectively (all p < 0.0001). Radioactive iodine treatment was more often given in patients who were less than 45 years of age, asymptomatic, and with metastasis only in the lung or bone only (p = 0.03, 0.11, 0.01). CONCLUSIONS: Longterm survival is possible in patients with distant metastasis from differentiated thyroid cancer. This retrospective study found that age of 45 years or more, site other than lung only or bone only, and symptoms at the time of diagnosis are associated with poorer outcomes.