OBJECTIVE: To describe a patient with longstanding depression and hypothyroidism who had marked mood improvement only after triiodothyronine (T3) was added to her thyroxine (T4) replacement therapy. CASE SUMMARY: A 50-year-old white woman had a long history of depression and documented hypothyroidism since 1991. Despite treatment with T4 with dosages up to 0.3 mg/d, she continued to be depressed, have symptoms of hypothyroidism, and have a persistently elevated thyroid-stimulating hormone concentration. Addition of a low dose of T3 to her regimen resulted in significant mood improvement. DISCUSSION: The relationship between hypothyroidism and depression is well known. It is possible that this patient's long history of depression may have been a consequence of inadequately treated hypothyroidism, due either to poor patient compliance or resistance to T4. Nevertheless, her depression responded to addition of a low dose of T3 to her regimen. This case emphasizes the importance of screening depressed patients for hypothyroidism. Her clinical course also suggests that depression related to hypothyroidism may be more responsive to a regimen that includes T3 rather than to replacement with T4 alone. This is consistent with the observation that T3 is superior to T4 as adjuvant therapy in the treatment of unipolar depression. CONCLUSIONS: Depressed patients should be screened for hypothyroidism. In hypothyroid patients, depression may be more responsive to a replacement regimen that includes T3 rather than T4 alone. Therefore, inclusion of T3 in the treatment regimen may be warranted after adequate trial with T4 alone.