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Presepsin (soluble cluster-of-differentiation 14 subtype [sCD14-ST]) is a humoral risk stratification marker for systemic inflammatory response syndrome and sepsis. It remains unknown whether presepsin can be used to stratify risk in elective cardiac surgery. The authors therefore determined the usefulness of presepsin for risk stratification in patients having elective cardiac surgery.Eight hundred fifty-six cardiac surgical patients were prospectively studied. Preoperative plasma concentrations of presepsin, procalcitonin, N-terminal pro–hormone natriuretic peptide, cystatin C, and the additive European System of Cardiac Operative Risk Evaluation 2 were compared to mortality at 30 days (primary outcome), 6 months, and 2 yr. Discrimination was assessed with C statistic. Logistic regression analysis was used to calculate univariable and multivariable odds ratios.Thirty-day mortality was 3.2%, 6-month mortality was 6.1%, and 2-yr mortality was 10.4% across the population. Median preoperative presepsin concentrations were significantly greater in 30-day nonsurvivors than in survivors: 842 pg/ml (interquartile range, 306 to 1,246) versus 160 pg/ml (interquartile range, 122 to 234); difference, 167 pg/ml (interquartile range, 92 to 301; P < 0.001). The results were similar for 6-month and 2-yr mortality. Compared to the European System of Cardiac Operative Risk Evaluation 2, presepsin concentration provided better discrimination for postoperative mortality at all follow-up periods, including 30 days (C statistic 0.88 vs. 0.74), 6 months (0.87 vs. 0.76), and 2 yr (0.81 vs. 0.74). Presepsin also provided better discrimination than cystatin C, N-terminal pro–hormone natriuretic peptide, or procalcitonin. Elevated presepsin remained an independent risk predictor after adjustment for potential confounding factors.Elevated preoperative plasma presepsin concentration is an independent predictor of postoperative mortality in elective cardiac surgery patients and is a stronger predictor than several other commonly used assessments.