OBJECTIVE Several biological markers have been studied for the differentiation of infection from disease activity in systemic lupus erythematosus (SLE) patients with discrepant results. We aimed to evaluate the role of serum presepsin, hs-CRP, procalcitonin (PCT), and copeptin (CPP) in differentiating bacterial infections from disease activity in SLE patients. METHODS This study is a cross-sectional observational study in which 94 Egyptian patients were recruited from June 2017 to January 2018. Our patients were divided into two groups: group (1) included 48 patients with active SLE hospitalized with any sort of lupus activity and group (2) included 46 patients with active SLE admitted with a proven bacterial infection. Hs-CRP, presepsin, PCT, and CPP were measured using enzyme-linked immune sorbent assay technique. RESULTS Hs-CRP, presepsin, PCT, and CPP were highly significantly higher among group (2) patients compared to group (1) patients (p < 0.001). Serum presepsin expressed higher specificity than hs-CRP (87.5% vs 60.4%) but the same sensitivity (80.4%) in the detection of bacterial infection in SLE patients. Serum PCT expressed higher specificity than hs-CRP (100% vs 60.4%) but lower sensitivity (73.9% vs 80.4%). Serum CPP expressed higher specificity than hs-CRP (65.9% vs 60.4%) but lower sensitivity (65.9% vs 80.4%). CONCLUSIONS Our study suggests that increased serum levels of hs-CRP, presepsin and PCT levels are useful in differentiating bacterial infections from disease activity in SLE patients. Serum CPP could be used as an adjunct with more specific inflammatory biomarkers in making better diagnostic judgments. CONCLUSIONS • The increased serum levels of hs-CRP, presepsin and PCT levels are useful in differentiating bacterial infections from disease activity in SLE patients. • Serum Presepsin expressed higher specificity than hs-CRP but the same sensitivity in the detection of bacterial infection in SLE patients. • Serum CPP expressed higher specificity than hs-CRP but lower sensitivity.