Background <p>Serum CXCL10 is one of the chemokines that is strongly associated with systemic lupus erythematosus (SLE) and its related complications, particularly lupus nephritis (LN). Our study aimed to validate serum CXCL10 as a potential biomarker of LN and disease activity, and to assess its association with organ damage in Egyptian patients.</p> Methods <p>A cross-sectional study was conducted among 100 SLE patients recruited from Ain Shams University Hospital, with 50 patients in group I (without LN) and 50 in group II (with LN). All patients underwent a medical history review, clinical examination, and assessment of disease activity using the SLE Disease Activity Index (SLEDAI-2K) and the Renal SLEDAI (R-SLEDAI). Damage scores were recorded for each patient. Laboratory investigations, such as serum CXCL10, complete blood count (CBC), blood urea nitrogen (BUN), serum creatinine, estimated glomerular filtration rate (eGFR), urine analysis, 24-h urinary protein excretion, antinuclear antibodies (ANA), anti-dsDNA antibodies, and serum complement (C3, C4).</p> Results <p>Serum CXCL10 levels were significantly elevated in patients with LN compared to those without (<i>p</i> &lt; 0.001). Disease activity indices, renal function parameters, and damage scores were all increased in the LN group (<i>p</i> &lt; 0.001). CXCL10 levels demonstrated strong positive correlations with 24-hour urinary protein, BUN, serum creatinine, disease activity and damage scores, and strong negative correlations with eGFR, C3, and C4 (all <i>p</i> &lt; 0.001). Diagnostic accuracy analyses showed that serum CXCL10 predicted LN with 96% sensitivity and 94% specificity and was also predictive of renal and overall disease activity (sensitivity/specificity for R-SLEDAI: 100%/94.2%; for SLEDAI-2K: 81.97%/97.44%).</p> Conclusion <p>Serum CXCL10 is a promising non-invasive biomarker for identifying LN and monitoring disease activity in SLE patients.</p>