Abstract Background: According to recent studies, in renal disease High Mobility Group Box 1 protien (HMGB1) levels in blood and urine, its expression in renal tissue, and its levels in the cytoplasm and extracellular medium are all elevated. Aim of Study: Was to assess serum and urinary levels of HMGB1 in correlation to renal histopathology, disease activity and organ damage in systemic lupus patients (SLE). Patients and Methods: Serum and urine levels of HMGB1 were measured in 25 SLE patients with active nephritis by ELISA at baseline (I) and after 6 months follow-up (II). Renal biopsies were performed at baseline. Results: There was high statistical significant difference between serum and urine HMGB 1 at baseline (I) and after follow-up (II) and between total BILAG score (I) and (II). There was statistically significant difference between SLE nephritis patients (responders and non responders) as regard total BILAG index, p < 0.001. There was statistical significant difference between different classes of renal biopsy regarding urinary level of High Mobility Box protein 1 (I), p < 0.05 with highest level in class V. At base line, there were no statistical difference between different categories of renal BILAG score as regard serum or urinary levels of high mobility box protein 1 (I), p>0.05. After follow-up, there was significant difference between patients with BILAG category A and C in serum (but not urinary) high mobility box protein 1 (II). There was significant positive correlation between total BILAG score after follow-up and serum level of High Mobility Box protein 1 (II) and SLICC score, p < 0.05. There was a significant positive correlation between renal BILAG score after follow-up and serum High Mobility Box protein 1 (II) after follow-up. There was a significant positive correlation between 24hrs urinary proteins and urinary level of High Mobility Box protein 1 (II) after follow-up p < 0.05. Conclusion: HMGB 1 levels (serum and/or urinary) are high in SLE patients with nephritis compared to reference range. There is an association/correlation not only between HMGB1 and general disease activity in SLE patients but also between it and renal disease activity, severity and class. It could be a useful marker of lupus nephritis activity and class that may influence therapeutic strategies replacing rebiopsy.