Osteopontin (OPN) is involved in the regulation of the immune response and is accused in the pathogenesis of several autoimmune diseases including systemic lupus erythematosus (SLE). An obvious link between OPN and T 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 the association of genotypes and alleles frequencies of OPN 9250 (rs1126616) and IL-17A 197 (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 sig- nificantly 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