BACKGROUND: Triiodothyronine (T3) augmentation in treatment-resistant depression had been successfully performed with both tricyclic as well as with SSRI antidepressants. In this paper, the efficacy of addition of moderate dose of l-thyroxine (T4) to serotonergic antidepressants in refractory depression was evaluated. METHODS: The study included 17 female patients, aged 30-60 years, with treatment-resistant depressive episode in the course of unipolar or bipolar mood disorder. All patients had no history of thyroid axis disturbances and had T3, T4, and thyroid-stimulating hormone (TSH) values within the normal range. The antidepressants preceding thyroxine augmentation were serotonergic antidepressants (clomipramine - 11 patients, paroxetine - 5 patients, fluoxetine - 1 patient). l-thyroxine was added in the dose of 100 microm daily for 4 weeks. RESULTS: After four weeks of l-thyroxine augmentation, the remission, assessed as 7 or less points on Hamilton Depression Rating Scale (HDRS) was obtained in eleven patients (64.7%). Five other patients (29.5%) had responded (reduction>50% on HDRS) and one patient did not show an improvement. The efficacy of augmentation did not show any correlation with laboratory tests' results performed before (T3, T4, TSH and TSH stimulation test) as well as with any clinical factors (age, diagnosis, duration of illness, duration of episode). CONCLUSIONS: The addition of moderate dose of l-thyroxine may be a successful augmentation strategy in female depressed patients in whom the effect of serotonergic antidepressant had been unsatisfactory. It may be efficient despite of the lack of disturbances of thyroid axis in such patients.