The immune and nervous systems are closely interrelated through their messenger molecules: cytokines, hormones and nitric oxide. There are sex differences in the magnitude of the inflam-matory response and one of the mechanism by which female sex steroids modulate the in-flammatory response could be through the hy-pothalamo-pituitary-adrenal axe (HPA axes). In this study, we aimed to investigate the in-ter-relationship between the different levels of estradiol hormone and the different inflamma-tory stimuli on the HPA axis response, and the role of interleukin 6 (IL6 ) and nitric oxide (NO). This was achieved by using 100 female albino rats divided in to 3 main groups: The first group was the sham group, which was used to test the effect of all sham procedures used in the study. The two other groups represented the two in-flammatory states: local (induced by formaline injection) and systemic (cecal ligation and puncture: CLP). Under each inflammatory state, the effect of intact ovary, estradiol treated ova-riectomy and placebo treated ovariectomy were studied. HPA responses were evaluated, 24 hours after the sham or the inflammatory pro-cedure, through the measurement of the plasma levels of Corticotropin-releasing Hormone (CRH), adrenocorticotropes Hormone (ACTH) and cor-tisol. Both IL6 and nitrite were also meas-ured.We found that high physiological levels of estradiol reduced the enhanced HPA response induced by different inflammatory mediators during systemic and local inflammation. With significant enhancement of the HPA response observed mainly during local inflammation. We conclude that both the levels of estradiol hor-mone and the type of inflammation seem to play an important determining role on HPA response. IL6 and NO play important roles that could ex-plain the previous findings.