Background: Multiple studies have demonstrated successful radioactive iodine remnant ablation (RRA) following preparation with recombinant human thyroid stimulating hormone (rhTSH). Short-term studies in relatively low-risk patients have also suggested that rhTSH-stimulated RRA can have an effective adjuvant therapy function in destroying residual microscopic thyroid cancer cells. However, very few of these studies have included a significant number of intermediate or high-risk patients. The goal of this study was to examine clinical outcomes after rhTSH stimulated RRA in a larger cohort of thyroid cancer patients at higher risk of recurrence and disease-specific mortality. Methods: A retrospective chart review identified 586 thyroid cancer patients prepared for RRA with either a thyroid hormone withdrawal (THW) (n=321) or rhTSH preparation (n=265). The primary end points included both the best response to initial therapy and the clinical status at final follow-up. Clinical outcomes were compared within each of the American Thyroid Association (ATA) risk groups (low, intermediate, and high) and American Joint Committee on Cancer (AJCC) stages (I-IV) based on the method of preparation for RRA (THW vs. rhTSH). Results: Preparation with rhTSH was more likely to be associated with an excellent response to therapy (39.4% for rhTSH vs. 30% for TWH, p=0.03) and fewer additional therapies (29% for rhTSH vs. 37% for TWH, p=0.05) than THW. However, after a median follow-up period of 9 years, the final clinical outcomes were not significantly different with respect to recurrence rates (1.5% for rhTSH vs. 1.2% for TWH), likelihood of having persistent disease (46% for rhTSH vs. 48% for THW) or likelihood of having no evidence of disease (53% for rhTSH vs. 52% for TWH). Furthermore, clinical outcomes were similar between rhTSH and THW preparation across all ATA risk groups and AJCC stages. Conclusions: rhTSH preparation for RRA is associated with a small, but statistically significant improvement in an initial response to therapy and similar final clinical outcomes across a wide range of risk of recurrence and risk of disease-specific mortality. These data suggest that rhTSH preparation for RRA can be effectively used in intermediate and high-risk patients without known distant metastases.