Estrogen sulfotransferase (EST, encoded by SULT1E1) catalyzes the sulfoconjugation and inactivation of estrogens. Despite decades of biochemical study and the recognition that high levels of estrogen sulfates circulate in the blood of pregnant and nonpregnant women, the physiological role of estrogen sulfation remains poorly understood. Here we show that ablation of the mouse Sult1e1 gene caused placental thrombosis and spontaneous fetal loss. This phenotype was associated with elevated free estrogen levels systemically and in the amniotic fluid, increased tissue factor expression in the placenta and heightened platelet sensitivity to agonist-induced activation ex vivo. Treatment of pregnant Sult1e1-null mice with either an anticoagulant or antiestrogen prevented the fetal loss phenotype. Our results thus identify Est as a critical estrogen modulator in the placenta and suggest a link between estrogen excess and thrombotic fetal loss. These findings may have implications for understanding and treating human pregnancy failure and intrauterine growth retardation.