Among vitamin K-dependent hemostatic regulatory proteins, protein Z plays a dual role, functioning as a cofactor for the protein Z-dependent protease inhibitor in the inhibition of activated factor X, while, on the other hand, promoting thrombin assembly on phospholipid membranes. Despite numerous studies exploring the physiological roles of protein Z, its precise function and clinical implications, particularly in thrombotic and hemorrhagic disorders, remain ambiguous. Conflicting findings regarding the association of protein Z deficiency with venous thrombosis and bleeding tendencies have been observed. Discussing the genetic polymorphisms that may influence protein Z levels and their correlation with clinical outcomes remains an open issue. Additionally, we present a detailed methodology for the quantitative assessment of protein Z antigen levels in plasma, highlighting the implications of various physiological and pathological conditions on its concentration.