Objective: To assess the role of TNFα-308 G/A and PTPN22 C1858T SNP with respect to SLE susceptibility in Egyptian patients and whether these genetic polymorphisms are associated with the clinical and immunological features of the disease. Also, determination of TNF alpha concenteration in relation to different genotypes and in relation to disease activity. Methods: 40 SLE patients & 40 healthy subjects were tested for TNF alpha -308 and PTPN22 (C1858T) genotypes by PCR-RFLP and TNFα concentration was measured in their serum using ELISA. Results: No significant differences in TNFα-308 and PTPN22 (C1858T) genotypes or alleles frequencies could be identified between SLE cases and controls (P=0.108, 0.152 respectively). The level of serum TNFα was significantly higher in SLE patients when compared with the healthy control volunteers (P < 0.001). Furthermore, TNFα serum level was also statistically significantly higher in SLE patients with cardiac affection, with vasculitis and with low complement level (P=0.045, 0.016, 0.015 respectively). The serum level of TNF was statistically significantly higher in SLE group with high disease activity when compared with those low disease activity (P = 0.001). Also, there was a significant positive correlation between serum TNFα and SLEDAI (r = 0.723, P < 0.001). Conclusion: The results of this study suggest that, TNFα -308 and PTPN22 (C1858T) polymorphisms, do not exhibit a significant influence on the susceptibility, disease course or laboratory characteristics in SLE in Egyptian patients. Nevertheless, serum TNFα level could be a sensitive marker of SLE disease activity.