Objective <p>This multicenter, open-label, randomized controlled trial (RCT) aims to assess the efficacy and safety of levothyroxine monotherapy in lowering the risk of cardiovascular disease (CVD) in untreated older adults with subclinical hypothyroidism (SCH) who are diagnosed according to population-specific TSH reference values.</p> Methods <p>A total of 254 patients with SCH who meet the diagnostic criteria will be recruited, and the baseline clinical data of the patients will be collected. Then, a total of 127 patients will be randomly divided into each of the treatment and control groups, and the treatment group will receive daily levothyroxine&#xa0;doses (Merck&#xa0;Euthyrox® levothyroxine 50 mcg&#xa0;tablet). Specifically, 50 µg of levothyroxine per day will be administered to patients in the treatment group (or 25 µg to patients with a body weight &lt; 50 kg) for at least 48 weeks to maintain thyroid-stimulating hormone (TSH) levels within the normal range. The participants in the control group will be subjected only to thyroid status evaluation, and the results will be recorded. The participants will complete five visits before and after the start of the trial, and differences in the change in carotid intima–media thickness (CIMT), maximum mean change in plaque burden, and changes in lipid profiles, bone mineral densities, and incidences of fatal and nonfatal cardiovascular events between the initial visit and the last follow-up visit will be evaluated via vascular ultrasound. </p> Discussion <p>We will explicitly address whether levothyroxine replacement therapy provides cardiovascular benefits for older adults with subclinical hypothyroidism.</p> Clinical trial registration <p>ClinicalTrials.gov, No. ChiCTR2400092634. Registered on 30 November 2024. Recruitment for this study began on December 1, 2024, and continues until at least until November 30, 2025.</p>