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We aimed to investigate whether serum cholinesterase (SChE) activity can be helpful for the diagnosis of septic shock and to evaluate its usefulness in comparison with procalcitonin (PCT) and C-reactive protein (CRP).A prospective single-blinded study conducted in an intensive care unit of university hospital. Patients were classified as having cardiogenic shock, septic shock, or hemorrhagic shock. We also included a control group without neither hemodynamic instability nor sepsis. For all included patients, SChE, PCT, and CRP were simultaneously sampled.The comparison of sepsis markers between all groups showed that the mean values of PCT and CRP were significantly higher in patients with septic shock. However, SChE activity was significantly lower in this group. The SChE activity was found to be more accurate than PCT and CRP for the diagnosis of septic shock. In fact, an SChE activity ≤ 4000 UI/L predicted the diagnosis of septic shock with a sensitivity of 78%, a specificity of 89%, a predictive negative value of 97%, and a predictive positive value of 65%. However, the prognostic value of SChE activity was poor in multivariate analysis.The SChE activity level was significantly decreased in patients with septic shock. However, its prognostic value is poor. Our results suggest that SChE activity is useful for the diagnosis of septic shock. Further studies are warranted to confirm our findings.