The antidepressant tianeptine has been shown to decrease the response of the hypothalamic-pituitary-adrenal (HPA) axis to stress and to attenuate the behavioral effects of the cytokine inducer, lipopolysaccharide (LPS). Since LPS also activates the HPA axis, the objective of this study was to assess the effects of tianeptine on the HPA axis activation and Fos expression induced by intraperitoneal (i.p.) administration of LPS (30 and 250 microg/kg respectively). Chronic, but not acute, tianeptine treatment (10 mg/kg twice a day for 15 days, i.p.) attenuated LPS-induced increase of plasma ACTH and corticosterone in rats bearing an indwelling catheter in the jugular vein and Fos immunoreactivity in the paraventricular nucleus (PVN). These results open new vistas on the pharmacological activity of tianeptine and provide further insights on the action mechanisms of antidepressants in clinics.