The present study was designed to determine whether an association exists between HPA activity and cytokine production in major depression (MD). In 9 patients with MD and 11 control subjects of both sexes, all drug-free, activity of the HPA axis was evaluated by circadian rhythm of plasma cortisol, 24-h free urinary cortisol, an overnight 1 mg dexamethasone suppression test, and an oCRF stimulation test. Spontaneous and LPS-stimulated production of IL-1β, IL-6, and TNFα by peripheral blood mononuclear cells were also determined. We found a significantly elevated spontaneous production of IL-6 in patients with MD (3541.2 ± 726.8 vs 380.4 ± 77.5 pg/mL in controls, p < 0.05), while LPS-stimulated production was significantly lower in patients than in control subjects (19,867.7 ± 3649.2 vs 33,142.2 ± 15,47.2 pg/mL, p < 0.05). The adrenocorticotropic hormone response to oCRF, evaluated as the area under the curve (AUCACTH) was significantly lower in patients than in control subjects (p = 0.