Activation of coagulation frequently occurs in severe infection and sepsis and may contribute to the development of multiple organ dysfunction. Factor V Leiden is a relatively common mutation resulting in a mild prohaemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with factor V Leiden may suffer from more severe coagulopathy in case of severe infection or sepsis. Aggravation of the procoagulant state in sepsis may subsequently result in more severe organ dysfunction and an increased risk of death. Here we discuss the experimental and clinical evidence regarding the relationship between the presence of a factor V Leiden mutation and the incidence and outcome of sepsis.