Summary. Background: Oral estrogen use is associated with changes in plasma levels of many coagulation proteins. Objective: To gain more insight into the underlying mechanism of estrogen-induced changes in coagulation. Methods: Ovariectomized female mice were used to study the impact of oral 17α-ethinylestradiol (EE) on plasma coagulation, hepatic coagulation gene transcript levels, and dependence on estrogen receptor (ER) α and ERβ. Results: Ten days of oral EE treatment resulted in significantly reduced plasma activity levels of factor (F)VIII, FXII, combined FII/FVII/FX and antithrombin, whereas FIX activity significantly increased. Regarding hepatic transcript levels, oral EE caused significant decreases in fibrinogen-γ, FII, FV, FVII, FX, FXII, antithrombin, protein C, protein Z, protein Z inhibitor and heparin cofactor II mRNA levels, whereas FXI levels significantly increased and transcript levels of FVIII, FIX, protein S and α2-antiplasmin remained unaffected. All EE-induced coagulation-related changes were neutralized by coadministration of the non-specific ER antagonist ICI182780. In addition, ERα-deficient mice lacked the EE-induced changes in plasma coagulation and hepatic transcript profile, whereas ERβ-deficient mice responded similarly to non-deficient littermate controls. A crucial role for the ER was further demonstrated by its rapid effects on transcription, within 2.5–5 h after EE administration, suggesting a short chain of events leading to its final effects. Conclusions: Oral EE administration has a broad impact on the mouse coagulation profile at the level of both plasma and hepatic mRNA levels. The effects on transcription are rapidly induced, mostly downregulatory, and principally mediated by ERα.