Introduction: Systemic lupus erythematosus (SLE) is a heterogenousautoimmune disease involving most immune cells. Many studies revealeda number of cytokine pathways that are important in the disease process.Among these are B- cell activating factor (BAFF) that regulates B-cellmaturation, survival, and function and is over expressed in a variety ofautoimmune diseases including SLE.Objective: To investigate the association between BAFF genepolymorphisms and the susceptibility to SLE.Methods: Fifty Egyptian SLE and thirty normal control subjects wereincluded in the study. Single nucleotide polymorphisms (SNPs) in theBAFF promoter region; 2841 (T>C), 2701 (T>A), 871 (C>T) wereinvestigated by PCR-RFLP genotyping.Results: The frequency of mutant alleles of both 871C>T and 2701A>T was higher among SLE patients than controls with significantdifference between patients and controls (p-value <0.001 and 0.000respectively). There is a high significant relation between 871 C>Tpolymorphism and SLE (P=0.000), with Sensitivity of the test=100 % andspecificity=70%. The patients expressing the 2701 A allele were 7 timesmore prone to SLE than those with T/T wild genotype with Sensitivity ofthe test =78%, specificity =66.7% & Odds ratio =7.09, C.I at 95%=2.29-22.64.Conclusion: Polymorphisms in the regulatory region of the BAFFgene do contribute to the susceptibility to SLE in Egyptian patients. Thiscorrelation points to BAFF as a candidate therapeutic target in SLE.