Thirty-nine patients with major depression were studied to determine the differential effects of desipramine (DMI) and fluoxetine (FLU) on thyroid hormones. Twenty-six percent showed some abnormality in baseline thyroid hormone levels. There were no demonstrable differences for any of the thyroid indices from baseline to the 3- or 6-week samples for the total group or for either drug by repeated measures analysis of variance. There was a significant group by time interaction for total thyroxine (TT4) between the drug treatment groups, which was caused by a small but significant increase in TT4 in the DMI sample. Correlations were performed between the change in hormones over the 6 week period and treatment response. There was a significant association between a decline in triiodothyronine (T3) levels and response to FLU but not DMI. The implications of these findings for the pathophysiology of depression and antidepressant drug mechanisms are discussed.