The strengths of this systematic review and meta-analysis include (1) the performance of presepsin was formally compared with PCT and CRP; (2) detailed subgroup analyses were utilized to solve the heterogeneity between the included studies; (3) different compositions of control groups (healthy control, non-infectious SIRS, and mixed) were compared in the subgroup analysis; (4) the timing of biomarker measurements and different specimen types were taken into account in the analysis; and (5) the optimal cut-off was attempted to be determined in this study. The gene discussed is CRP; the disease is systemic inflammatory response syndrome.