Background: The role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in immunopathogenesis of systemic lupus erythematosus (SLE) was previously documented. Neutropenia and nephritis are common features in SLE patients and have been hypothesized to be due to accelerated apoptosis induced by binding of death receptor ligands like TRAIL to their cognate receptors on sensitive cells. Objectives: The aim of this study was to determine the serum concentration of soluble TRAIL (sTRAIL), the expression level of TRAIL mRNA in the peripheral blood mononuclear cells (PBMC) and expression level of TRAIL receptor-1 (TRAIL-R1, death receptor-4/DR-4/CD261) on polymorphonuclear leucocytes and to clarify their relation with disease activity, neutropenia and renal impairment in SLE patients. Methodology: The study enrolled 25 patients with active SLE, 25 patients with mild or no disease activity, 25 patients with Rheumatoid arthritis and 15 age and gender-matched healthy volunteers as a control group. Serum level of circulating TRAIL was measured by ELISA, the expression level of TRAIL mRNA on PBMC was determined by Quantitative Real-Time reverse transcription-polymerase chain reaction and flow cytometry was applied to evaluate the expression level of TRAIL R1 on polymorphonuclear leucocytes among the study population. Results: Serum level of sTRAIL was significantly (P<0.001) higher in patients with active SLE than those with no activity, Rheumatoid arthritis and healthy controls. Up-regulation of TRAIL mRNA expression in the PBMN cells and TRAIL R1 expression on neutrophils was detected in active lupus patients with a statistically significant difference (P<0.001) compared to other participants. A statistically significant correlation was detected between sTRAIL, TRAIL mRNA and TRAIL R1 expression and SLE activity, neutropenia and nephritis (P<0.001).The sensitivity, specificity, PPV, NPV and accuracy of TRAIL mRNA were 80%, 60%, 66.7%, 75% and 70% respectively. Conclusion: Concentration of circulating TRAIL and TRAIL mRNA levels could be potential markers for SLE activity assessment and predictors of lupus-associated neutropenia and renal affection.