Abstract Background: Systemic Erythematosus (SLE) is a chronic, complicated and challenging disease to diagnose and treat. The etiology of SLE is unknown, but certain risk factors have been identified that lead to immune system dysregulation with pathogenic autoantibody formation and immune complex deposition. Am of Study: To assess blood concentration of CD5+ B cells in patients with SLE and to evaluate their relationship with SLE disease activity. Patients and Methods: The present study included forty SLE patients who were selected from outpatient clinic of Rheumatology and Rehabilitation of Ain Shams University Hospital and diagnosed according to new EULAR and ACR classification criteria. Based on SLEDAI, the patients were selected and divided into two groups. The first group included 20 patients with inactive disease and the second group included 20 patients with active disease. They were matched with ten healthy individuals as a control group, and all were subjected to full history, clinical examination, ESR, CRP, serum com-plements, anti-dsDNA, ANA, serum creatinine twenty-four hours urinary proteins as well as CD5+ B lymphocytes by flow cytometric analysis. Results: In the present study, the percentage of CD5+ B lymphocytes per total lymphocytes were significantly de-creased in SLE patients compared to healthy individuals. Moreover, the percentage of CD5+ B lymphocytes per total B cells were significantly decreased in SLE patients compared to controls. We also have found a statistically highly significant decrease in the percentage of CD5+ B cells in active SLE patients compared to inactive patients. As regards the corre-lation studies, the results revealed a positive correlation between CD5+ B cells and each of platelets, C3 and C4. Moreover, the diagnostic performance of CD5+ B cells was evaluated and our results showed that CD5+ B cells can discriminate SLE patients from controls, and can predict the disease activity. Conclusion: The proportions of CD5+ B cells were sig-nificantly decreased in SLE patients than normal people, and were significantly decreased in active SLE patients than inactive ones. These findings denote that CD5+ B cells may have a potential role in preventing autoimmunity development.