Background : Systemic lupus erythematosus patients have a lot of autoantibodies that are directed against elements of the blood and proteins complexed to phospholipids, which in turn lead to hypercoagulability and a thrombosis-prone state, consequently, it may lead to acquired protein S deficiency because of the presence of anti- protein S antibodies.Objective : To determine the presence of circulating anti–protein S (anti-PS) antibodies in Egyptian patients with SLE and correlate their presence with protein S activity, the presence of antiphospholipid antibodies and the occurrence of thrombotic events.Patients & Methods: The study included 30 Egyptian SLE female patients. As well as, 30 normal individuals of matched age and sex as a control group. Total and free protein S levels were estimated by LIATEST® PROTEIN S test system, protein S activity was estimated using the STACLOT® PROTEIN S test system, and the presence of anti-protein S antibodies was determined by ELISA technique.Results: The patients age had a mean of 25.80 years ± 6.88 years, the mean age of disease onset was 21.48 years ± 6.40 years, and a mean disease duration of 4.32 years ± 3.27 years. The levels of total PS, free PS and PS activity was significantly lower in patients than in controls. 26.66% of patients had free PS deficiency, 40% of patients had total PS deficiency, and PS activity was deficient in 90% of cases. Anti-protein S antibodies were present in 9 patients (30%), the prevalence of antiphospholipid antibodies was significantly higher in PS-Ab positive patients (66.6%) than in the negative ones (19%), moreover the incidence of venous thrombosis was significantly higher in anti-PS-Ab positive patients (55.5%) than in the anti-PS-Ab negative patients (4.76%). No significant difference in PS levels was found between anti-PS-Ab positive patients and negative ones. Conclusion: Protein S deficiency in systemic lupus erythematosus patients is not solely caused by anti-protein S antibodies; and that these antibodies may contribute with or through the antiphospholipid antibodies in altering protein S activity resulting in a prethrombotic state.