Systemic lupus erythematosus (SLE) is a multifactorial chronic inflammatory autoimmune connective tissue disease. Lupus nephritis (LN) is a common and serious complication of SLE which can progress to end-stage renal disease. Renal biopsy is the gold standard in the diagnosis and classification of LN, but since it is an invasive procedure, it is neither desirable nor applicable for all cases. This has led to the search for an alternative, noninvasive, site-specific, and immune process-related biomarkers. Uromodulin (Tamm-Horsfall glycoprotein) is the most abundant urinary protein expressed exclusively by the thick ascending limb cells and released into urine of healthy controls. Studies showed that it may act as a danger signaling molecule eliciting an inflammatory response following conditions that damage the nephron integrity and leading to uromodulin release into the interstitial space. This study aimed to assess uromodulin as a screening biomarker of tubulointerstitial involvement in patients with SLE and to elucidate its correlation with disease activity and progression. The study was conducted on 70 patients divided into two groups: control group (Group I) consisted of 20 apparently healthy volunteers of comparable age and sex to the patients’ group, and 50 SLE patients (Group II) diagnosed according to the 2012 Systemic Lupus Collaborating Clinics (SLICC) classification criteria. Group II was further subdivided into 23 patients without manifestations of LN (Group II A) and 27 patients with manifestations of LN (Group II B). Urinary uromodulin level showed statistically significant difference among the studied groups, being lowest among the LN patients with a mean value 5.6 ± 3.4, in SLE patients without nephritis 9.9 ± 5.2 and 12.9 ± 4.6 in the control group. Urinary uromodulin also correlated positively with estimated glome- rular filtration rate. A negative correlation was found between urinary uromodulin and serum creatinine, 24 h urinary proteins and SLICC renal activity score. No statistically significant correlation was found between urinary uromo- dulin and SLE disease activity index. Thus, decreasing urinary uromodulin levels can be a marker for renal involvement and tubulo- interstitial nephritis in active SLE patients and a marker for chronic kidney disease and nephron loss in the absence of activity markers.