COAGULATION factor V is a critical cofactor for the activation of prothrombin to thrombin, the penultimate step in the generation of a fibrin blood clot^1,2. Genetic deficiency of factor V results in a congenital bleeding disorder (parahaemophilia) ³, whereas inheritance of a mutation rendering factor V resistant to inactivation is an important risk factor for thrombosis^4,5. We report here that approximately half of homozygous embryos deficient in factor V (Fv^−/−), which have been generated by gene targeting, die at embryonic day (E) 9–10, possibly as a result of an abnormality in the yolk-sac vasculature. The remaining Fv^−/− mice progress normally to term, but die from massive haemorrhage within 2 hours of birth. Considered together with the milder phenotypes generally associated with deficiencies of other clotting factors^6,7, our findings demonstrate the primary role of the common coagulation pathway and the absolute requirement for functional factor V for prothrombinase activity. They also provide direct evidence for the existence of other critical haemostatic functions for thrombin in addition to fibrin clot formation, and identify a previously unrecognized role for the coagulation system in early mammalian development.