ACTIVATED protein C (APC) is a serine protease with potent anti-coagulant properties, which is formed in blood on the endothelium from an inactive precursor1. During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and Villa (ref. 2). To do this efficiently the enzyme needs a non-enzymatic cofactor, protein S (ref. 3). Recently it was found that the anticoagulant response to APC (APC resistance) 4 was very weak in the plasma of 21% of unselected consecutive patients with thrombosis5 and about 50% of selected patients with a personal or family history of thrombosis6,7; moreover, 5% of healthy indi-viduals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis5. Here we demonstrate that the phenotype of APC resistance is associated with hetero-zygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC. The allelic fre-quency of the mutation in the Dutch population is ~2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref. 8), protein S (ref. 9), antithrombin10 deficiency) together.