Aim: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by a wide variety of autoantibodies, some of which are pathogenic. In recent years it has become more evident that the polyclonal B cell activation in SLE is T-cell dependent. To investigate whether serum levels of TNF-α and IL-6 is higher in Egyptian patients with SLE- presented with lupus nephritis -than healthy control volunteers and its correlation with the clinical activity in patients with different activity scores as measured by Systemic Lupus Erythmatosus Disease Activity Index (SLEADI). Methods: Sixty individuals (40 patients with SLE and 20 healthy control volunteers) were the subject of this study, they were subjected to thorough clinical examination, laboratory investigations, their clinical disease activity was scored according to SLEDAI, and serum sampling was obtained for TNF-α and IL-6 levels assay. Renal biopsy was carried out for all patients. Results: The mean level of TNF-α was (766.95±357.82 ρg/ml) for patients with active disease while it was (314.01±100.87ρg/ml) for those with inactive disease -the difference was statistically significant (p=0.002), and (172.7±39.19ρg/ml) for the healthy control group. The mean level of IL-6 was (135.4±54.23ρg/ml) for patients with active disease while it was (47.33±18.61ρg/ml) for those with inactive disease - the difference was statistically significant (p=0.002), and (21.15±10.99ρg/ml) for the healthy control group. A significant correlations between TNF-α and IL-6 serum levels and the SLEDAI score was observed (r =0.743 and 0.772 respectively). Conclusion: Serum TNF-α and IL-6 are sensitive markers for SLE disease activity. They may be useful independent markers for prediction of SLE disease activity and to differentiate normal subjects from those having SLE. Their possible therapeutic implications in the treatment of SLE in the future deserve wide scale trials.