Background <p>Systemic lupus erythematosus (SLE) is a multisystemic disease, caused by a variety of factors. Osteopontin (OPN) is a pleiotropic protein, important in bone remodeling and immune system signaling. The variant rs1126616 of <i>osteopontin (OPN) gene</i> has been associated with over expression of OPN which plays important role in pathogenesis of immune-mediated diseases. Also, tumor necrosis factor like weak inducer of apoptosis (TWEAK), was found to be up-regulated in the blood and urine of individuals with lupus nephritis (LN), suggesting its potential as a biomarker for LN. This study aimed to detect the association of the (rs1126616) variant of the <i>OPN</i> gene, serum level of OPN and urinary level of TWEAK in SLE patients and LN among a&#xa0;group of Egyptian females.</p> Methods <p>Case control study which included 90 participants, 60 SLE patients were clinically confirmed, of which 30 were SLE without nephritis, 30 were SLE with nephritis, and 30 apparently healthy individuals as a control group. The rs1126616 variant of <i>OPN</i> gene was genotyped using Taqman Real-Time PCR, also level of serum osteopontin, and urinary TWEAK were measured by ELISA.</p> Results <p><i>OPN</i> gene variant rs1126616 was observed to be statistically significant&#xa0;different&#xa0;between the SLE group and control group (<i>P</i> value = 0.022). There was a statistically significant increase in serum OPN level in SLE cases compared to control group (<i>P</i> &lt; 0.001). Regarding u TWEAK /creatinine ratio, it was statistically higher in the LN cases compared to SLE without nephritis and the control group (<i>P</i> value = 0.047, 0.001 respectively).</p> Conclusion <p><i>OPN</i> rs1126616 and serum OPN level may play a role in pathogenesis of SLE. uTWEAK/creatinine ratio could be a good diagnostic marker for L.N.</p>