['Recent trial results have revived interest in low-activity initial (131)I therapy (RIT) of differentiated thyroid cancer (DTC).', 'This study sought to compare different initial (131)I activities for outcome.', 'A database study was performed in a University hospital.', '1298 DTC patients were included (698 low risk, 434 high risk M0, and 136 M1), grouped according to ablation activity (I, ≤ 2000 MBq [54 mCi]; II, 2000-3000 MBq [54-81 mCi]; and III, >3000 MBq [81 mCi]), subdivided by age (<45 and ≥ 45 y at diagnosis).', 'Complete remission (CR, defined as thyroglobulin [Tg] below functional sensitivity combined with visually negative (131)I diagnostic whole-body scintigraphy), recurrence, DTC-specific mortality, and relative survival rates were studied.', 'Low-risk patients: In patients <45 years, a lower median cumulative activity was required to achieve CR in group III (3590 MBq) than in groups I (8050 MBq) and II (6300 MBq). In patients at least 45 years of age, DTC-specific mortality was significantly higher in group I than in groups II and III (15-y: 16.1 ± 7.7%, 0.8 ± 0.8%, and 7.2 ± 5.5%, respectively; P = .004). High-risk M0 patients: In patients at least 45 years of age, the recurrence rate (15-y: 44.4 ± 16.6%, 24.1 ± 7.6%, and 8.6 ± 3.9%; P = .001) and DTC-specific mortality (15-y: 51.8 ± 15.8%, 13.2 ± 4.4%, and 9.5 ± 3.7%; P = .004) were significantly higher in group I than in groups II and III. M1 patients: There were no significant differences in survival results between different activity groups in either age category.'] Is long-term survival in differentiated thyroid cancer worse after low-activity initial post-surgical 131I therapy in both high- and low-risk patients?