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. The stimulation of the autoantibody producing B cells is likely mediated by the TH2 subtype of T cells producing IL-4, IL-5, IL-6 and IL- 10, whereas the TH1 subtype secreting IL-2 and IFN-γ predominates in cell-mediated immune response. Tumor Necrosis Factor (TNF-α) is both a proinflammatory and an immunoregulatory cytokine. TNF-α has differential effects on B cells, on T cells and on dendritic cells as well as on the process of programmed cell death. Understanding how the immune system integrates the pleiotropic properties of TNF-α is a challenge, particularly so in diseases like SLE. Meanwhile the role of IL-6 in the pathogenesis of SLE is controversial. Objective: To investigate whether serum levels of TNF-α and IL-6 is higher in Egyptian patients with SLE 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 Systemic lupus Erythmatosus 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 and examined by light microscopy by a pathologist blinded with the clinical activity. Results: The mean level of TNF-α was (766.95 ± 357.82 Pg/ml) for patients with active disease while it was (314.01 ± 100.87 Pg/ml) for those with inactive disease and (172.7 ± 39.19 Pg/ml) for the healthy control group. The difference was statistically significant (P = .002). The mean level of IL-6 was (135.4 ± 54.23 Pg/ml) for patients with active disease while it was (47.33 ± 18.61 Pg/ml) for those with inactive disease and (21.15 ± 10.99 Pg/ml) for the healthy control group. The difference was statistically significant (P = .002). A significant correlations between TNF-α and IL-6 serum levels and the SLEDAI score was observed (r = .743 and .772, respectively). Conclusion: Serum TNF-α and IL-6 are sensitive markers of SLE disease activity. They may be useful independent markers for prediction of SLE disease activity and to differentiate normal subjects from those having SLE. Possible therapeutic implications in the treatment of SLE in the future deserve wide scale trials.