Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with a high prevalence of cardiovascular disease due to accelerated atherosclerosis, as well as an increased risk of venous thromboembolism. Many of these clinical features have been attributed to the high prevalence of autoantibodies that are directed against phospholipid-bound antigens and that induce prothrombotic effects and disturb endothelial cell function. We conducted a case-control study in a cohort of female patients with SLE and in age-matched and sex-matched normal individuals. Patients had significantly higher levels of plasma inflammatory markers, but their overall coagulation status assessed by prothrombin fragment 1 + 2 and D-dimer plasma levels was not different from controls. Resistance against activated protein C (APC), assessed by a thrombin generation-based as well as an activated partial thromboplastin time-based method, however, was increased in patients. This defect was neither due to factor V Leiden carriership or to the use of oral contraceptives. This acquired form of APC resistance was due to proinflammatory changes associated with lower plasma levels of free protein S. In conclusion, acquired APC resistance may be an important determinant of the risk of thrombosis in patients with SLE, probably due to an active cross-talk between inflammation and coagulation systems.