Objective: Early diagnosis of sepsis is essential for bundle treatment. The purpose of this study was to determine the clinical significance of presepsin in sepsis related organ failure in the emergency department compared to other inflammatory markers. Methods: This was a retrospective review. Enrolled patients were divided into three groups, namely non-infectious organ failure, sepsis, and septic shock groups. The efficacy of presepsin, procalcitonin, and C-reactive protein (CRP) in discriminating sepsis were compared among the three patient groups. The presepsin, procalcitonin, and CRP levels were compared between 28-day survivors and non-survivors among those with sepsis. Results: A total of 277 patients with organ failure were included. The areas under the receiver operating characteristic curve (AUROCs) of presepsin, procalcitonin, and CRP for differentiating sepsis from non-infectious organ failure were 0.622, 0.777, and 0.809, respectively. The areas under the curve (AUCs) of presepsin, procalcitonin, and CRP for differentiating sepsis from septic shock were 0.717, 0.667, and 0.609, respectively. The AUCs of presepsin, procalcitonin, and CRP for predicting sepsis related mortality were 0.743, 0.635, and 0.632, respectively. Sepsis patients with high presepsin levels had a higher mortality than those with lower presepsin levels. Conclusion Presepsin is a good marker to differentiate septic shock from sepsis and predict mortality. CRP can aid the differential diagnosis of non-infectious causes in patients with organ failure.