The clinical usefulness of presepsin for discriminating between bacterial and nonbacterial infections (including systemic inflammatory response syndrome) was studied and compared with procalcitonin (PCT) and interleukin-6 (IL-6) in a multicenter prospective study. Suspected sepsis patients (n = 207) were enrolled into the study. Presepsin levels in patients with systemic bacterial infection and localized bacterial infection were significantly higher than in those with nonbacterial infections. In addition, presepsin, PCT, and IL-6 levels in patients with bacterial infectious disease were significantly higher than in those with nonbacterial infectious disease (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). The area under the receiver operating characteristic curve was 0.908 for presepsin, 0.905 for PCT, and 0.825 for IL-6 in patients with bacterial infectious disease and those with nonbacterial infectious disease. The cutoff value of presepsin for discrimination of bacterial and nonbacterial infectious diseases was determined to be 600 pg/ml, of which the clinical sensitivity and specificity were 87.8 % and 81.4 %, respectively. Presepsin levels did not differ significantly between patients with gram-positive and gram-negative bacterial infections. The sensitivity of blood culture was 35.4 %; that for presepsin was 91.9 %. Also there were no significant differences in presepsin levels between the blood culture-positive and -negative groups. Consequently, presepsin is useful for the diagnosis of sepsis, and it is superior to conventional markers and blood culture.