Abstract Background: Systemic lupus erythematosus (SLE)is an auto-immune, multi-system disease with female predominance. The difference in clinical manifestations, autoantibody profile and comorbidities between males and females has always been a subject of major debate. Aim of Study: To study the gender difference in SLE between a uniform group of the same ethnicity in respect to clinical manifestations, comorbidities, disease activity, damage, and mortality. Material and Methods: A retrospective study was con-ducted on 559 patients with SLE (58 males and 501 females) following at the Rheumatology and Rehabilitation Department, Faculty of Medicine, Cairo University Hospitals. The patients' demographic data, clinical manifestations, laboratory investi-gations, co-morbidities and medications received as well as SLE disease activity index (SLEDAI) at the first, last visit for each patient and accumulated damage according to Sys-temic Lupus International Collaborative clinics/American College of Rheumatology Damage Index (SLICC/ACR DI), were recorded. Results: The present study included 559 SLE patients, 58 males (10.4%) and 501 females (89.6%) with mean age of 32.3±9.1 years. Constitutional manifestations, serositis, lupus nephritis, renal failure and Anti-double stranded DNA antibody positivitywere higher in male SLE patients (p-value: 0.04, p-value: 0.045, p-value: 0.023, p-value: 0.002 and p-0.03 re-spectively), while hematological manifestations were more frequent in females (p-value: 0.04). SLEDAI at last visit SLICC DI and mortality were statistically higher in male SLE group. Conclusion: Gender differences exist between male and female SLE patients regardless of ethnic, age and duration variabilities with tendency towards more active disease, higher accumulated damage, and higher mortality in males with SLE.