Summary. Background: The endothelial protein C receptor (EPCR) binds protein C and enhances its activation. Anti-EPCR autoantibodies are found in patients with antiphospholipid syndrome and may explain the increased risk of thrombosis in these patients. Anti-EPCR autoantibodies have been associated with fetal death and myocardial infarction in young women. Objectives: To determine whether anti-EPCR autoantibodies are associated with deep vein thrombosis (DVT). Patients/methods: We measured plasma anti-EPCR autoantibody levels in the Leiden Thrombophilia Study (LETS), a population-based case–control study consisting of 474 patients with a first DVT and 474 control subjects. Results: The estimated risk of DVT was increased approximately 2-fold in the presence of elevated IgA, IgG or IgM anti-EPCR autoantibodies (i.e. levels above the 90th percentile as measured in the control subjects). The risk conferred by anti-EPCR increased in a dose-dependent manner for IgA and IgG. When anti-EPCR autoantibodies were considered in the co-presence of lupus anticoagulant (LAC) the odds ratio (OR) was 6.1 [95% CI 1.3–27.9]. Anti-EPCR without LAC remained associated with DVT (OR 1.6; 95% CI 1.2–2.1). Anti-EPCR autoantibodies were associated with high levels of D-dimer and soluble EPCR in controls, suggestive of a prothrombotic status induced by the autoantibodies. Conclusions: This study demonstrates that the presence of anti-EPCR autoantibodies is a moderate risk factor for DVT in the general population.