Background: Anti-nucleosome antibodies are a wide group of autoantibodies targeting the native nucleosome, which contribute to systemic lupus erythematosus (SLE) development. Objective: This study aimed to assess the anti-nucleosome antibodies as a diagnostic predictor to lupus nephritis (LN), to evaluate its sensitivity and specificity, and changes in titers with LN treatment. Patients and methods: The current research was conducted at Zagazig University Hospitals, Internal Medicine Department. A total of 60 SLE patients were involved in this survey. They were split into two groups: Group I consisted of 30 SLE patients without renal disease, and group II comprised of 30 individuals with lupus nephritis (LN). Group I was subdivided according to results of renal biopsy into (group Ia) with free kidney biopsy (n=17) and (group Ib) with class II/III LN (n=13). Results: SLE cases with pathological abnormalities in kidney biopsy, including those with (group II) and without clinical LN (group Ib or silent LN) showed significantly higher anti-nucleosome antibody titers. After therapy, there was a significant drop in group II's anti-nucleosome antibody titer and 24-hour urine proteins. Anti-nucleosome antibodies sensitivity for prediction of abnormal renal biopsy was 95.3%, specificity was 94.5%, while for prediction of proteinuria sensitivity was 80%, and specificity was 80%. Conclusion: Anti-nucleosome antibodies were more specific and sensitive than anti-dsDNA antibodies for diagnosing LN and early prediction of renal affection. Anti-nucleosome antibodies have valuable importance in following the response to treatment in LN.