BACKGROUND: L-thyroxine does not improve hypothyroid symptoms among adults with subclinical hypothyroidism (SCH). However, those with greater symptom burden before treatment may still benefit. OBJECTIVE: To determine whether L-thyroxine improves hypothyroid symptoms and tiredness among older adults with SCH and greater symptom burden. DESIGN: Secondary analysis of the randomized, placebo-controlled trial TRUST (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial). (ClinicalTrials.gov: NCT01660126). SETTING: Switzerland, Ireland, the Netherlands, and Scotland. PARTICIPANTS: 638 persons aged 65 years or older with persistent SCH (thyroid-stimulating hormone level of 4.60 to 19.9 mIU/L for >3 months and normal free thyroxine level) and complete outcome data. INTERVENTION: L-thyroxine or matching placebo with mock dose titration. MEASUREMENTS: 1-year change in Hypothyroid Symptoms and Tiredness scores (range, 0 to 100; higher scores indicate more symptoms) on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire among participants with high symptom burden (baseline Hypothyroid Symptoms score >30 or Tiredness score >40) versus lower symptom burden. RESULTS: 132 participants had Hypothyroid Symptoms scores greater than 30, and 133 had Tiredness scores greater than 40. Among the group with high symptom burden, the Hypothyroid Symptoms score improved similarly between those receiving L-thyroxine (mean within-group change, -12.3 [95% CI, -16.6 to -8.0]) and those receiving placebo (mean within-group change, -10.4 [CI, -15.3 to -5.4]) at 1 year; the adjusted between-group difference was -2.0 (CI, -5.5 to 1.5; P = 0.27). Improvements in Tiredness scores were also similar between those receiving L-thyroxine (mean within-group change, -8.9 [CI, -14.5 to -3.3]) and those receiving placebo (mean within-group change, -10.9 [CI, -16.0 to -5.8]); the adjusted between-group difference was 0.0 (CI, -4.1 to 4.0; P = 0.99). There was no evidence that baseline Hypothyroid Symptoms score or Tiredness score modified the effects of L-thyroxine versus placebo (P for interaction = 0.20 and 0.82, respectively). LIMITATION: Post hoc analysis, small sample size, and examination of only patients with 1-year outcome data. CONCLUSION: In older adults with SCH and high symptom burden at baseline, L-thyroxine did not improve hypothyroid symptoms or tiredness compared with placebo. PRIMARY FUNDING SOURCE: European Union FP7.