SummaryA new anticoagulant system involving a serpin has been recently characterised. The protein Z/Z‐dependent protease inhibitor (PZ/ZPI) system inhibits activated factors X, XI and IX by different mechanisms. By homology with other anticoagulant systems (antithrombin or the protein C/protein S), deficiency of the serpin (ZPI) or its cofactor (PZ) might imbalance the haemostatic system with thrombotic consequences. Evidence supports the in vivo anticoagulant role of this complex and the thrombotic consequences of its deficiency. Non‐sense variations of the ZPI (W303X and R67X) have been associated with increased risk of venous thrombosis. Moreover, PZ deficient mice carrying the FV Leiden have a thrombotic phenotype. Finally, some reports suggest that PZ deficiency might increase the risk of thrombosis. However, other studies question the thrombotic relevance of both ZPI and PZ deficiencies. This system could play a redundant role in haemostasis that explains the conflicting results on its thrombotic potential, which might be exacerbated in combination with other prothrombotic factors.