Context: the regulation of the circulating levels of TNF-related apoptosis-inducing ligand (TRAIL), a cytokine of the TNF family, playing a key role in the immune-surveillance against cancer, is incompletely understood. Objective: to investigate the potential link between TRAIL and 17-β estradiol. Design, Setting and Participants: circulating TRAIL levels were measured by ELISA in plasma samples (n=246) of healthy age-matched (range 30-70 years) men and women and in sera (n=180) of female belonging to different physio-pathological conditions (childhood, pregnancy, under gonadotropin treatment, menopause) characterized by different levels of circulating 17-β estradiol. Results: TRAIL plasma levels in women with age <50 years were significantly lower compared with age-matched men, while in woman ≥50 years old TRAIL levels were significantly higher compared to the age-matched men and to the younger women. Moreover, analysis of women with different conditions revealed a significant inverse correlation between the serum levels of TRAIL and 17-β estradiol, with the lowest levels of TRAIL being observed during pregnancy, and the highest in childhood and in postmenopausal. Moreover, gonadotropin treatment in women undergoing assisted reproduction was accompanied by an acute decrease of serum TRAIL levels. Finally, in vitro treatment with 17-β estradiol decreased TRAIL expression levels in peripheral blood mononuclear cells. Conclusions: Our data suggest that 17-β estradiol plays a role in regulating TRAIL circulating levels. The demonstration that post-menopausal women exhibit the highest TRAIL levels is of particular interest in light of a previous large study population, showing that TRAIL is positively correlated to the overall survival.