A total of 62 patients with major depressive disorder were analyzed in the study. Patients were evaluated for 11 weeks in an open label design to investigate the differential effects of reboxetine, sertraline and venlafaxine on thyroid hormones. Serum thyrotrophin (TSH), thyroxine (T4) and free (f)T4 levels were measured before and after treatment. All groups showed significant improvement in HAM-D scores. TSH level significantly reduced and T4 level significantly increased in the reboxetine group, however TSH level significantly increased and T4 level significantly reduced in the sertraline group. Percent changes of TSH (p=0.007) and T4 (p=0.001) were significantly different between the reboxetine and sertraline groups. In the sertraline group, baseline TSH levels were correlated with response to treatment as determined by the change in HAM-D scores (p=0.03, r=0.648). There was a significant association between the percent changes in TSH values and the reduction in HAM-D scores in the reboxetine group (p=0.03, r=-0.434). In the whole study group, female patients had lower values of basal T4 compared with men (p=0.043), however percent changes of T4 did not differ between genders. In the treatment-responders significant increase in the reboxetine group and significant decrease in the sertraline group regarding the T4 values were found. We observed that various antidepressants had different effects on thyroid hormone levels and this could be attributed to the different mechanisms of actions of these antidepressants.