It has been suggested that interactions between hypothalamic pituitary adrenal (HPA) axis and serotonin-1A (5-HT1A) receptor system are involved in the pathophysiology of major depression. Pharmacologic challenge test with 5-HT1A receptor agonists is a useful approach to study the sensitivity of 5-HT1A receptors in depressed patients and the interaction of these systems. A cross-sectional case-control study was designed to assess the effect of the 5-HT1A receptor agonist, buspirone, on 5-HT1A receptor function in 30 patients with major depression (DSM-IV) and in 30 age- and sex-matched healthy controls. Depressed patients showed a basal score in the Hamilton Rating Scale for Depression (HRSD) higher than 17. After the administration of a single oral dose of buspirone (30 mg), corticotrophin (ACTH), cortisol, and prolactin (PRL) peak response minus baseline (Δ) and area under the curve (AUC) were evaluated. No significant difference in the hormonal response between depressed patients and controls was observed. No correlation with the severity of depression (HRSD score) was found. These results indicate no consistent changes in the hormonal response to the 5-HT1A agonist buspirone in depressed patients. Therefore, this study does not support the hypothesis of an altered postsynaptic 5-HT1A receptor function in major depression. Copyright © 2007 John Wiley & Sons, Ltd.