Osteopontin (OPN) is involved in the regulation of the immune response and is accused in the pathogenesis of several autoimmunediseases including systemiclupuserythematosus (SLE).AnobviouslinkbetweenOPNandT cells, particularly T helper 17 cells is reported, where OPN produced by dendritic cells supports interleukin-17 (IL-17) expression, contributing to pathology of autoimmune disorders. The aim of the study was to investigate theassociation ofgenotypesandallelesfrequenciesofOPN9250(rs1126616) andIL-17A197(rs2275913) genes polymorphisms with their serum levels, susceptibility, disease activity and severity in Egyptian SLE patients. A total of 80 SLE patients and 80 healthy subjects were enrolled. The PCR-RFLP technique was used to detect OPN 9250 C/T and IL-17A 197 G/A genes polymorphisms. Serum OPN and IL- 17 levels were measured by the enzyme-linked immunosorbent assay. OPN TT genotype and T allele were significantly detected in SLE patients more than controls (P=0.003, P < 0.001 respectively). IL-17A AA genotype showed non-significant higher frequency in SLE patients than in their controls (P=0.07). While only the A allele of IL-17A polymorphism was significantly elevated in patients (P=0.048). There was statistical significant association between OPN CT and TT genotypes and both renal and mucocutaneous manifestations. Also IL-17A AG and AA genotypes was significantly associated with renal, mucocutaneous in addition to the hematological manifestations. Serum OPN levels were significantly increased with TT genotype while serum IL-17 levels were significantly increased with AA genotype. Disease activity and severity scores were significantly elevated with both OPN TT and IL-17A AA genotypes. In conclusion, OPN 9250 C/T and IL-17A 197 G/A genes polymorphisms and their serum levels seemed to have a role in pathogenesis of SLE.