Background: Systemic Lupus Erythematosus (SLE) is a chronic multisystem autoimmune disease that is highly heterogeneous in its presentation. Effective SLE patient care relies on serological biomarkers. There is high interest in the identification of autoantibodies other than Antinuclear Antibodies (ANA) and anti-double stranded DNA (Anti-dsDNA). Aim: To evaluate the use of antinucleosome (Anti-NCS) antibody as a single marker to detect disease activity and renal involvement in SLE patients. Methods and Material: This case-control study was carried out in Clinical Pathology Department at Assiut University Hospital in the period from 2014 to 2017. It included 92 patients. Sixty-two patients were diagnosed as SLE. Thirty patients had connective tissue diseases other than SLE (non-SLE). Twenty apparently healthy subjects were taken as controls. All subjects were tested for ANA, anti-dsDNA antibody and Serum anti-NCS antibody on Alegria ® (OR-GENTEC Diagnostic GmbH-Germany). Statistical analysis: Date entry and data analysis were done using SPSS Version 19, Chicago, USA (Statistical Package for Social Science). Results: There was higher significant elevation in the level of anti-NCS antibodies than anti-dsDNA in SLE patients in comparison to those with non-SLE and control groups.In LN patients anti-NCS antibodies were highly elevated than anti-dsDNA comparing to non LN patients. Anti-NCS antibodies had a stronger correlation than anti-dsDNA antibodies with SLEDAI score. In 22 negative anti-dsDNA SLE patients, 13 (59.1%) were positive for anti-NCS. Anti-NCS antibodies showed higher sensitivity and specificity than anti-dsDNA in SLE and LN patients. Conclusion: Anti-nucleosome antibodies is highly sensitive and specific in diagnosis of SLE, especially if anti-dsDNA antibodies are absent. Anti-NCS antibodies are good disease activity markers for the assessment of SLE and LN disease activity.