Introduction: Systemic lupus erythematosus (SLE) is considered an autoimmune disorder that influence many organs, distinguished by complement activation, synthesis of many autoantibodies, organ damage, and deposition of immune complex. Objective: Examine the relationship between the interferon regulatory factor 5 (IRF5) gene's genetic polymorphism and lupus nephritis disease activity as well as the correlation between SLE and these conditions. Patients and methods: Sixty-three children were included and classified into three groups as follows: 21 children with lupus nephritis (LN), 21 lupus children without nephritis, and 21 control cases. Blood samples from all children were tested for the IRF5 gene (rs2004640) polymorphism utilizing the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Results: Cases and controls differed in high statistically significant way regarding the frequency of TT genotype (64.3% and 23.8% respectively with p value <0.001) and frequency of risk allele T (77.4% and 38.1% respectively with p <0.001). However, when it came to IRF5 genotypes and alleles, there was no statistically significant difference between those with and without nephritis. Conclusion: Children in Egypt who have the rs2004640 T allele and TT genotype may be at increased risk of developing SLE. Egyptian children with SLE who carry the rs2004640 T allele or TT genotype do not have an increased risk of developing nephritis.