Endotoxin is a potent activators of the hypothalamic-pituitary-adrenal (HPA) axis. However, sex hormones can modulate HPA response to local and systemic inflammation. We used female rats divided in to 3 main groups: group I, Sham group. Group II cecal ligation and puncture (CLP) and group III local inflamed .Each of group II and III further sudivided in to female rats with intact ovary, ovariectomized female rats which either received estradiol, progesterone or vehicle. Our study in the rats showed that the HPA responses to systemic inflammation (CLP) and local inflammation (formalin injection in hind paw) were enhanced by gonadectomy and attenuated by either estradiol (E2) or progesterone replacement. In addition, the inflammatory cytokine IL6 and mediator NO affected by the levels of sex hormones. Thus, both E2 and progesterone appear to play an important role in modulation of inflammation and further investigation is needed to clarify the underlying mechanism.