INTRODUCTION: Estetrol (E4) is a natural human estrogen with selective action in different tissues. A combined oral contraceptive (COC) with E4 15 mg and Drospirenone (DRSP) 3mg is in Phase 3 trials. Here, we report its effects on hemostatic markers. METHODS: In this IRB-approved, randomized, open-label study, women received E4 15 mg/DRSP 3mg (n=38), ethinyl-estradiol (EE) 30 mcg/Levonorgestrel-(LNG) 150 mcg (n=29) or EE-20 mcg/DRSP-3 mg (n=31). We compared changes of hemostasis parameters between baseline and cycle 6 with a P<.05 considered significant. RESULTS: Pro-coagulant factors increased similarly in E4/DRSP, EE/LNG and EE/DRSP users for fibrinogen (+10%, +5% and +16%, respectively) and prothrombin (+7%, +13% and +7%, respectively). Anti-coagulant factors decreased significantly less with E4/DRSP and EE/LNG compared to EE/DRSP for Protein S activity (-4%, -5% and -30%, respectively) and free Protein S antigen (+5%, -3%; and -23%, respectively). The fibrinolysis marker, tissue-plasminogen activator, changed significantly more favorably with E4/DRSP than EE/LNG or EE/DRSP (-7%, -33% and -40%, respectively). Prothrombin fragment 1+2, a marker of ongoing coagulation, changed significantly less with E4/DRSP than other COCs (+23%, +71% and +64%, respectively). Endogenous thrombin potential (ETP) activated protein C resistance (APCr) increased significantly with EE/LNG (+78%) and EE/DRSP (+121%) compared to E4/DRSP (+3.0). CONCLUSION: Coagulation parameter changes over 6 months demonstrate mostly similar changes for E4/DRSP and EE/LNG, both of which are less thrombogenic than EE/DRSP. For some factors, primarily anticoagulant and fibrinolysis markers, ETP-APCr, and prothrombin fragment 1+2, E4/DRSP is more favorable than EE/LNG. The differences between E4/DRSP and EE/DRSP demonstrate that the choice of estrogen is important when considering thrombosis risk.