© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org. BACKGROUND: Fatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue. METHOD: This study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged =65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 µg (25 µg if weight <50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose. RESULTS: Among 230 participants, the mean ± standard deviation (SD) TSH was 6.2 ± 1.9 mIU/L at baseline and decreased to 3.1 ± 1.3 with LT4 (n = 119) versus 5.3 ± 2.3 with placebo (n = 111, p < .001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI -1.8 to 2.1; p = .88), or mental fatigability (-1.0; 95% CI -2.8 to 0.8; p = .26). In participants with higher fatigability at baseline (=15 points for the physical score [n = 88] or =13 points for the mental score [n = 41]), the adjusted between-group differences at 1 year were 0.4 (95% CI -3.6 to 2.8, p = .79) and -2.2 (95% CI -8.8 to 4.5, p = .51). CONCLUSIONS: Levothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability.