Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis, related to the lupus anticoagulant or anticardiolipin antibodies (ACL). Antithrombin (AT), protein C (PC) and protein S are natural anticoagulants with a very important role in the regulation of coagulation and fibrinolysis, and in the prevention of thrombosis. Total protein S (TPS), free protein S (FPS), AT and PC were measured in 53 unselected patients with SLE in order to verify their relation with previous history of thrombosis or the presence of anticardiolipin antibodies (ACL). The influence of prednisone use on the concentration of these natural anticoagulants was also analysed. The control group was formed by 20 blood donors. The PC concentration was increased in patients with ACL, when compared to controls (p < 0.01), or patients without ACL (p = 0.01). FPS levels were decreased in patients with SLE in relation to controls (p = 0.01), but not related to thrombosis or ACL. There was no difference in plasmatic concentration of AT and TPS, between patients and controls. PC, AT and TPS were increased in patients under prednisone use (p < 0.01). There was no association between concentration of natural anticoagulants and a history of thrombosis. Although decreased FPS was found, or results suggest that it seems not to be a risk factor for thrombosis in SLE. Since PC and AT were not decreased, they should not be involved with thromboembolic complications in these patients. The use of prednisone can influence concentration of natural anticoagulants in patients with SLE.