Many adults aged 60 years or older take the thyroid hormone levothyroxine, which is generally continued for life. However, it is uncertain whether long-term continuation is always necessary. To determine the percentage of adults aged 60 years or older who can successfully discontinue levothyroxine treatment. This single-group, prospective study included community-dwelling adults aged 60 years or older who were taking levothyroxine at a stable dosage (≤150 µg/d) for at least 1 year and had a thyrotropin (TSH) level of less than 10 mIU/L. The study was conducted at 58 general practices in the Netherlands. Participants were enrolled between January 2020 and July 2022 and final follow-up occurred on December 12, 2023. Open-label, protocol-driven, stepwise dose reduction with thyroid function testing performed at least 6 weeks after each reduction in levothyroxine dose. The primary outcome was the proportion of participants who discontinued levothyroxine and had both a thyrotropin level of less than 10 mIU/L and a free thyroxine level within the reference range at 1 year after the start of discontinuation. The secondary outcomes included factors associated with successful discontinuation (demographics, thyroid function, dose) and thyroid-related quality of life. Of the 370 participants who started the levothyroxine discontinuation phase (median age, 70 [range, 60-89] years; 80% female; median thyrotropin level, 2.2 [range, 0.02-9.69] mIU/L; mean free thyroxine level, 1.21 [SD, 0.18] ng/dL), 366 completed final follow-up at 1 year. Of the 370 participants (median levothyroxine dose at baseline, 50 [range, 12.5-150] µg/d), 95 (25.7% [95% CI, 21.5%-30.4%]) successfully stopped taking levothyroxine and had a median thyrotropin level of 5.03 mIU/L (range, 1.56-9.40 mIU/L) and a mean free thyroxine level of 1.01 ng/dL (range, 0.80-1.43 ng/dL) at 1 year. Of the 95 participants who successfully discontinued levothyroxine, 46 (48.4% [95% CI, 38.6%-58.3%]) had a thyrotropin level of less than 4.8 mIU/L. Among the 88 participants taking a levothyroxine dose of 50 µg/d or lower, 56 (63.6%) successfully discontinued this treatment. Thyroid-related quality of life showed no clinically relevant changes overall from baseline to 1 year and stratified by successful levothyroxine discontinuation vs unsuccessful discontinuation. In this open-label, single-group prospective study, 25.7% of adults aged 60 years or older discontinued levothyroxine treatment while maintaining adequate thyroid function at 1 year. Evaluation of the need to continue levothyroxine should be considered in adults aged 60 years or older, particularly in those taking a dose of 50 µg/d or lower.