To assess the possible association between the protein tyrosine phosphatases non-receptor 22 (PTPN22) gene 1858 CT polymorphism and the predisposition to systemic lupus erythematosus (SLE) in Egyptian patients and its influence on clinical and laboratory parameters. PTPN22 gene 1858 CT polymorphisms were analyzed in forty SLE patients and 20 normal controls by real-time polymerase chain reaction (PCR) technology, using the TaqMan 5-allele discrimination assay. Detailed history, clinical examination, and investigations were done to detect various organ involvement. The homozygous genotype TT was absent in both SLE and controls. The CC genotype was observed in 47.5% SLE and 80% controls; the CT genotype was found in 52.5% patients and 20% controls. The frequencies of the C and T alleles were 74 and 26% in SLE and 90 and 10% in controls, respectively. The presence of CT genotype increased the risk for developing SLE by 4.42. Renal involvement was significantly higher in SLE patients with CT (76.2%) compared to those with CC genotype (42.1%).