Objective: Depressive mood consequent to hypothyroidism can be reversed with levothyroxine (LT4) replacement therapy. However, it is unclear whether increasing LT4 dose confers additional mood benefits. Design and Patients: A single-blinded before-and-after study of 24 patients with hypothyroidism who were aged 65 years or older and undergoing LT4 replacement therapy with stable doses. Measurements: Geriatric Depression Scale (GDS-K) and Hyperthyroid Symptom Scale (HSS-K) were assessed at baseline, 3 months after increasing LT4 dose by an additional 12.5 µg/d, and finally 3 months after returning to the baseline dose. Results: Serum thyroid-stimulating hormone (TSH) concentrations decreased at the higher LT4 dose (1.95 ± 2.16 vs 0.47 ± 1.09 mIU/L, P <.001) and recovered after returning to the baseline dose. Serum-free thyroxine levels and HSS-K scores were unchanged during the study period. GDS-K scores improved on the increased dose (9.5 ± 6.6 vs 7.5 ± 4.7, P =.029), and this improvement was maintained after returning to the baseline dose (9.5 ± 6.6 vs 7.4 ± 5.4, P =.010). Higher serum TSH was independently associated with both higher GDS-K and depression risk among those with depressive mood (GDS-K > 10) at baseline. Conclusions: Depressive mood improves with increased LT4 dose, without significant hyperthyroid symptoms or signs, in older adults undergoing thyroid hormone replacement. These findings suggest the potential for varying the treatment target for hypothyroidism based on mood status and that low-dose LT4 treatment might be an ancillary treatment for depression.