Protein Z-dependent protease inhibitor is a protein circulating in the blood which inhibits factors Xa and XIa of the coagulation cascade. It is a member of the class of the serine protease inhibitors (serpins). Its name implies that it requires protein Z, another circulating protein, to function properly, but this only applies to its inhibition of factor X.

It is about 72 kDa heavy and 444 amino acids large. It is produced by the liver.Water et al. found deficiency of ZPI in 4.4% of a cohort of patients with thrombophilia (a tendency to thrombosis).Han et al. first described ZPI in 1998. The same group further characterised it in 2000.