Our laboratory recently found a novel mechanism for thrombophilia, which is characterized by an inherited resistance to activated protein C (APC). The APC-resistance test, which measures the anticoagulant response to APC in an activated partial thromboplasin time (APTT) reaction, was devised and used to screen a cohort of consecutive thrombosis patients. APC-resistance was found in approximately 40% of the cases. Other known causes for thrombosis, such as deficiencies of protein C, protein S or antithrombin, were found in another 5% of the patients. Our results, which have recently been confirmed from other laboratories, suggest APC-resistance to be highly prevalent in thrombosis patients. In a majority of cases, APC-resistance was demonstrated to be inherited and family studies revealed an autosomal dominant mode of inheritance. In the investigated families, APC-resistance was associated with thrombosis, which suggests a causal relationship between APC-resistance and thrombosis. An anticoagulant cofactor activity, which corrected APC-resistance, was found in normal plasma, whereas plasma from an individual with pronounced APC-resistance was devoid of this activity. Purification and characterization of the novel APC-cofactor suprisingly revealed that it was identical to coagulation factor V. Thus, factor V is not only an important procoagulant, but also expresses anticoagulant properties as a cofactor to APC. Our present data suggest the anticoagulant function to be a property of unactivated factor V, whereas the procoagulant activity is expressed after activation to Va. APC-resistant individuals have normal levels of procoagulant V-activity, it is now known that APC-resistance is caused by mutation in the factor V gene changing arginine 506 to a glutamine, thus affecting the APC-cleavage site.