Background: Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine (¹³¹I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with ¹³¹I therapy. Methods: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2±9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0mL; range 31.9-242.2mL) were randomized to receive placebo (n=32), 0.01mg MRrhTSH (n=30), or 0.03mg MRrhTSH (n=33) 24 hours before a calculated ¹³¹I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. Results: At six months, TV reduction was enhanced in the 0.03mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44±12.7% (SD) in the placebo group, 41±21.0% in the 0.01mg MRrhTSH group, and 53±18.6% in the 0.03mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03mg MRrhTSH group, the subset of patients with basal ¹³¹I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03mg MRrhTSH group (13.4±23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01mg, and 0.03mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. Conclusions: When used as adjuvant to ¹³¹I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤0.03mg, indicating that the lower threshold for efficacy is around this level.