Abstract The aim of this study was to determine whether glutathione peroxidase (GSH-Px) activity in endometrial tissue is regulated by sex hormones and to compare the GSH-Px activity of normal and cancerous endometrium. The localization of GSH-Px in human normal endometrium and endometrial cancer was determined immunohistochemically. GSH-Px activity was assayed in endometrial tissue obtained from women with endometrial cancer and age-matched controls, as well as in rat uterine tissue. GSH-Px immunoreactivity was localized in the glandular epithelium of normal human endometrium and reached a maximum in the late proliferative and early secretory phases of the menstrual cycle. In spayed rats, uterine GSH-Px activity was significantly increased by exogenous estrogen ( P< 0.01) and significantly reduced by exogenous progesterone ( P< 0.01). GSH-Px activity in endometrial cancer tissue was significantly higher ( P< 0.01) than that in endometrial tissue from age-matched healthy controls. Among endometrial cancer tissues, a significant increase in GSH-Px activity was associated with well-differentiated rather than moderately or poorly differentiated adenocarcinoma ( P< 0.01), with slight rather than marked myometrial invasion ( P< 0.01), and with the presence of concurrent endometrial hyperplasia ( P< 0.01). These results show that endometrial GSH-Px activity is regulated by sex hormones, being stimulated by estrogen and suppressed by progesterone, and that the level of GSH-Px activity in endometrial cancer tissue may be a significant prognostic factor.