Systemic lupus erythematosus (SLE) is an autoimmune disease with complex etiology. Systemic lupus erythematosus (SLE) is an autoimmune disease with complex etiology. Genetic aberrations disrupting the immune regulatory mechanisms may initiate autoimmune disease development. Recent studies have proved that the interferon regulatory factor 5 (IRF5) gene is an important risk factor for SLE. We aimed to investigate the association of the rs2004640 polymorphism within the IRF5 gene with SLE and lupus Nephritis and SLE activity in a sample of adult Egyptian population. 199 individuals were classified into: group I: included 118 patients who were further subdivided into 57 patients with and 61 patients without lupus nephritis respectively and group II: 81 healthy subjects as controls. Genotyping of the SNP rs2004640 at IRF5 gene was analyzed via allele discrimination assay using Real-Time PCR. TT genotype was the most abundant among SLE patients (p=0.001), but GG genotype was the most abundant in controls (p=0.001) while, genotype frequency showed no significant statistical difference between lupus patients with and without nephritis (p= 0.2, 0.1 respectively). The multivariate analysis of prediction of SLE activity [assessed by systemic lupus erythematosus disease activity index (SLEDAI) scoring] showed that the protein/creatinine ratio (95% CI, 0.001 to 0.002) and anti-dsDNA (95% CI, 0.005 to 0.1) were independent factors of SLE activity (OR=0.001 and 0.008 respectively). IRF5 gene polymorphism (rs2004640) might be candidate risk factor for developing SLE but not risk factor for lupus nephritis or the disease activity in a sample of adult Egyptian population.