To elucidate the roles of the ABO blood group, von Willebrand factor (vWF), and clotting factor VIII in the process of deep-vein thrombosis we undertook a population-based patient-control study in which 301 consecutive patients younger than 70 with a first, objectively diagnosed episode of venous thrombosis and without an underlying malignant disorder were compared with 301 healthy controls matched for age and sex. In univariate analysis, blood group, vWF concentration, and factor VIII concentrations were all related to deep-vein thrombosis. The risk of thrombosis increased with increasing vWF or factor VIII concentration and was higher in subjects of non-O blood groups than in those of group O. In multivariate analysis only factor VIII remained as a risk factor, and the dose-response relation between factor VIII concentration and risk of thrombosis persisted (subjects with factor VIII concentrations above 1500 IU/L had an adjusted odds ratio of 4.8 [95% Cl 2.3-10.0]). By contrast, the adjusted odds ratio for each vWF stratum did not differ from 1, and that for blood group was 1.5 (1.0-2.2). Our findings point to an effect on thrombosis risk of vWF and blood group, the former fully and the latter at least partly mediated through factor VIII. The 25% prevalence of factor VIII concentrations above 1500 IU/L among unselected consecutive thrombosis patients and the high adjusted relative risk for thrombosis lead to the conclusion that high factor VIII concentrations are common and represent a clear increase in risk of thrombosis, similar to the risks conferred by deficiencies of the coagulation-inhibiting proteins and activated protein C resistance.