Background: Although irritable bowel syndrome (IBS) is more common in women, little is known about the role of hormonal changes and menopause in IBS. Aim of the study: To examine the effect of female sex hormones on serum inflammatory parameters, histopathological and immunohistochemical changes in colonic mucosa associated with stress induced IBS in rat model of menopause. Material and Methods: Sixty female albino rats were divided into six groups (10 rats each): control sham ovariectomized (OVX), sham OVX / IBS, OVX/ IBS, OVX/ IBS/ Estrogen treated, OVX/ IBS /progesterone treated and OVX/ IBS /estrogen + progesterone treated groups. Two months after ovariectomy, rats were received hormonal replacement for consecutive 14 days and subjected to water avoidance stress (1 h) for 10 days. Serum histamine, serotonin and IL8were estimated, distal colon was processed for histopathological and immunohistochemical examination. Results: There were significant increases in serum levels of IL8 and histamine while a significant drop in serotonin levels besides a marked disturbance in colonic mucosal structure with significant elevated claudin 1 protein levels in IBS /OVX rats compared to others. Conclusion: Female replacement hormones were found to attenuate inflammatory markers and mucosal disturbance associated with IBS in a rat model of menopause.