Protein Z (PZ) is a 6.2 kDa vitamin K-dependent protein, synthesized in the liver. The gene for human PZ is localized to chromosome 13 at band 34 q. The structure of PZ is very similar to that of factors VII, IX, X and protein C. Very low plasma levels of protein Z were observed under oral anticoagulant treatment. The cause of this phenomenon might be increased protein Z binding on the surface of endothelial cells. Protein Z is consumed during coagulopathy. About 60% of humans suffering from a bleeding tendency of unknown origin presented with decreased plasma levels of protein Z. PZ forms a Ca(2+)-dependent complex with activated factor X (Xa) on phospholipid surfaces, that leads to the inhibition of factor Xa and decrease in thrombin generation. Inhibition of factor Xa may be caused directly by protein Z or indirectly by the activity of protein Z-dependent protease inhibitor (ZPI). ZPI is a 72 kDa member of the serpin family of proteinase inhibitors, synthesized in the liver. ZPI circulates in plasma in complex with protein Z. ZPI in the presence of Ca2+ and phospholipids inhibits factor Xa. The presence of protein Z enhances this process by more than 1000 times. ZPI also inhibits activated factor XI in the absence of protein Z, Ca2+ or phospholipids. Protein Z deficiency may induce bleeding as well as prothrombotic tendencies and might occur as an inherited disorder. Protein Z deficiency may aggravate mild bleeding tendency in subjects with diagnosed borderline decrease in von Willebrand factor and factor VII activity. Patients presenting with factor V Leiden mutation and low protein Z levels show earlier onset and higher frequency of thromboembolic events comparing to patients with normal protein Z levels.