This chapter examines the cardiovascular safety implications of combined hormonal contraceptives (CHCs), with a focus on their effects on coagulation. CHCs, widely used for contraception, are associated with an increased risk of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. The risk varies depending on the type and dosage of estrogen and progestogen components. Ethinylestradiol (EE), the most common synthetic estrogen in CHCs, significantly alters coagulation pathways, contributing to a pro-thrombotic state. Efforts to reduce these risks include lowering EE doses and introducing natural estrogens, such as estradiol (E2) and estetrol (E4). These natural estrogens demonstrate a more favorable safety profile, with less impact on coagulation factors and a reduced VTE risk. This chapter details how CHCs influence hemostatic pathways by increasing procoagulant factors, reducing anticoagulants, and modifying fibrinolysis. It highlights epidemiological studies and meta-analyses comparing natural and synthetic estrogens, demonstrating that E2- and E4-based formulations pose significantly lower thrombotic risks. The findings underscore the need for individualized risk assessments in contraceptive counseling and advocate for the use of advanced screening tools, such as the endogenous thrombin potential-based APC resistance assay, to better predict thrombotic risks. Additionally, this chapter discusses pharmacovigilance data, emphasizing the role of natural estrogens in improving contraceptive safety. These findings support the paradigm shift toward prescribing natural estrogen-based CHCs as first-line options. This chapter concludes by stressing the importance of precision medicine and patient-centered approaches in contraceptive care to balance efficacy, safety, and individual preferences.