Background: Subclinical hypothyroidism (SCH) is an increasingly common biochemical diagnosis made by finding mildly elevated thyroid stimulating hormone (TSH) yet normal thyroxine levels, affecting up to 200 in 1000 adults, of whom 135 will have nonspecific symptoms and the rest will have no symptoms at all. Following clinical practice guidelines from endocrine societies, SCH is often treated with levothyroxine (LT4). The prevalence of LT4-treated SCH has doubled from 1996 to 2006. More strikingly, LT4 has become the most prescribed drug in the U.S., surpassing opioids. However, no benefits of LT4 have been demonstrated on quality of life (QoL) or thyroid-related symptoms and little or no effect on cardiovascular events or mortality for patients with SCH. Yet, ~50% of patients older than 65 who take LT4 develop iatrogenic hyperthyroidism, increasing their risk for arrhythmias, angina pectoris, bone loss, and fractures. Based on this evidence, a guideline panel recently formulated a strong recommendation against routine LT4 use in most adults with SCH. Significance/Impact: There is clear evidence for overdiagnosis and overtreatment of patients with SCH, causing a substantial and unnecessary economic and treatment burden, and even harm. Once started, 9 in 10 patients with SCH continue LT4 therapy indefinitely. There is no evidence regarding the acceptability, feasibility, safety, and effects on QoL of discontinuing LT4 therapy among patients with SCH who have been previously started on LT4 therapy. Our study, consistent with the VA HSR&D priority area: Quality/Safety, will address these knowledge gaps and has the potential to improve the care delivered to thousands of Veterans. Innovation: This is the first study evaluating the acceptability and feasibility of discontinuing LT4 therapy among patients with treated SCH. This is also the first pilot randomized, double-blind, placebo-controlled trial to evaluate the safety and effects on QoL of discontinuing LT4 therapy in patients with SCH. Successful completion of this novel work will lay the foundation for the implementation of evidence-based care for Veterans with SCH and will contribute to addressing the national epidemic of LT4 overuse. Specific Aims: We propose a pilot study to address the following interrelated hypotheses: LT4-treated SCH is a highly prevalent condition among Veterans. Discontinuation of LT4 for Veterans with SCH will be feasible, acceptable, and safe, and will not negatively affect their QoL. In this proposal we aim to: 1) Identify the prevalence of LT4-treated SCH among Veterans. 2) Evaluate the feasibility of LT4 discontinuation among Veterans with SCH and determine the changes in QoL measures, blood lipids, and adverse events. 3) Assess the acceptability of LT4 discontinuation among Veterans with SCH and LT4-prescribing clinicians. Methodology: We will conduct a retrospective cohort study using the Corporate Data Warehouse through the VA Informatics and Computing Infrastruc...