Objectives: The autoimmune disease systemic lupus erythematosus (SLE) presented with many clinical symptoms, transcription factor fork head box protein 3 (Foxp3) is expressed on T-reg cells and essential for its development and function. Functional SNPs in the Foxp3-3279 (rs3761548 C/A) gene influence SLE pathogenesis. We aim to assess the relation between the functional polymorphism in Foxp3-3279 (rs3761548 C/A) gene and risk of SLE development and lupus disease activity state. Methods: This was a case-control study in which SLE patients were diagnosed according to American College of Rheumatology / Systemic Lupus International Collaborating Clinics (ACR/ SLICC) classification criteria. The degree of disease activity was assessed by Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS). Foxp3-3279 (rs3761548 C/A) gene polymorphism was detected using polymerase chain reaction restriction fragment length polymorphism-based analysis (PCR-RFLP). Results: We found that AA and AC genotypes significantly increased risk of SLE by 7.25 and 2.88 folds, respectively and A allele significantly increased that risk by 3.12 folds. AA genotype significantly increased risk of SLE moderate–severe disease activity and risk of lupus nephritis by 33.6 folds. Conclusion: Foxp3 -3279 (rs3761548 C/A) gene polymorphism was associated with the risk of SLE and lupus nephritis. The relation of this SNP with SLE disease activity highlighted the role of Foxp3 gene in SLE pathogenesis and manifestations that could potentially enhance the management of SLE patients by identifying each person's unique response to treatment.