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Inflammatory biomarkers may aid to distinguish between systemic inflammatory response syndrome (SIRS) vs. sepsis. We tested the hypotheses that (1) presepsin, a novel biomarker, can distinguish between SIRS and sepsis, and (2) higher presepsin levels will be associated with increased severity of illness and (3) with 28-day mortality, outperforming traditional biomarkers.Procalcitonin (PCT), C-reactive protein (CRP), presepsin, and lactate were analyzed in 60 consecutive patients (sepsis and SIRS, n=30 per group) on day 1 (D1) to D3 (onset sepsis, or after cardiac surgery). The systemic organ failure assessment (SOFA) score was determined daily.There was no difference in mortality in sepsis vs. SIRS (12/30 vs. 8/30). Patients with sepsis had higher SOFA score vs. patients with SIRS (11±4 vs. 8±5; p=0.023), higher presepsin (AUC=0.674; p<0.021), PCT (AUC=0.791; p<0.001), CRP (AUC=0.903; p<0.0001), but not lactate (AUC=0.506; p=0.941). Unlike other biomarkers, presepsin did not correlate with SOFA on D1. All biomarkers were associated with mortality on D1: presepsin (AUC=0.734; p=0.0006; best cutoff=1843 pg/mL), PCT (AUC=0.844; p<0.0001), CRP (AUC=0.701; p=0.0048), and lactate (AUC=0.778; p<0.0001). Multiple regression analyses showed independent associations of CRP with diagnosis of sepsis, and CRP and lactate with mortality. Increased neutrophils (p=0.002) and decreased lymphocytes (p=0.007) and monocytes (p=0.046) were also associated with mortality.Presepsin did not outperform traditional sepsis biomarkers in diagnosing sepsis from SIRS and in prognostication of mortality in critically ill patients. Presepsin may have a limited adjunct value for both diagnosis and an early risk stratification, performing independently of clinical illness severity.