The effect of amitriptyline on hypothalamic-pituitary-adrenocortical (HPA) axis activity was compared with that of fluvoxamine in 38 patients suffering from DMS-IV major depressive disorder. Basal plasma adrenocorticotropic hormone and cortisol levels were determined in the so-called "observation window" of an hour (08:00-09:00 h), and cortisol levels were determined again at 20:00 h. Clinical and biochemical assessments were performed before therapy (T0), at day 14 (T14), and at day 42 (T42) of the course of antidepressant treatment. At T0, neuroendocrine parameters did not differ in patients from those in controls, except for the ratio between cortisol levels at 20:00 h and the mean level of the "window" (ratio F20/F8), which was significantly higher, suggesting a dysregulation of the circadian pattern of cortisol. Although a decrease in the ratio F20/F8 was already apparent at T14 of both treatments, the repeated measures analysis of variance failed to demonstrate a significant variation with time (T0, T14, and T42) and with treatment (amitriptyline and fluvoxamine) for any hormonal measure. At T42, both treated groups showed a similar level of clinical improvement. Our results did not demonstrate any effect of antidepressant therapy on the cortisol circadian rhythm abnormality.