Aims:The aim of this study was to evaluate the association between TNF-a gene polymorphism (308 G/A) and SLE in Egyptian population and evaluate the relation among this polymorphism with the activity and the clinical manifestations of SLE. Subjects and methods: A case control study was performed on 50 female patients with systemic lupus erythematosus (mean age, 32.4±8.6 years) and 50 female healthy volunteers (mean age, 31.9±8.3 years) served as a controls. Genotyping was carried out by polymerase chain reaction, PCR products were digested by NcoI restriction enzyme. The digested PCR product was fractionated on 3% Agarose gel and visualized after staining by ethidium bromide. Results: TNF (rs1800629) GA+AA genotypes and A allele were significantly increased in studied SLE patients when compared to healthy control subjects (p=0.023, 0.007 respectively), with high risk to develop SLE (OR=1.959, 95% CI=1.097-3.501; OR=3.020, 95% CI=1.319-6.914 respectively). TNF genotypes showed significant differences between various SLEDAI activity grades (p=0.012). Moreover, GG genotype had significantly lower incidence of renal disorders and persistent proteinuria when compared to AG or AA (p=0.006, 0.001 respectively). While AA genotype showed significantly higher neurologic disorder when compared to GG and AG (