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The diagnosis of infection in critically ill patients is challenging because traditional markers of infection are often misleading. For example, serum concentrations of calcitonin pre-cursors are increased in patients with infections. However, their predictive accuracy for the diagnosis of sepsis in unselected patients in a medical intensive care unit (ICU) is unknown. Therefore, we compared the usefulness of serum concentrations of calcitonin precursors, C-reactive protein, interleukin-6, and lactate for the diagnosis of sepsis in consecutive patients suffering from a broad range of diseases with an anticipated stay of ≥ 24 hrs in a medical ICU.Prospective cohort study.Medical intensive care unit in a university medical center.101 consecutive critically ill patients.None.Blood samples were collected at various time points during the course of the disease. Systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock were diagnosed according to standardized criteria, and patients were reclassified daily without prior knowledge of the serum concentrations of calcitonin precursors or interleukin-6. At admission, 99% of the patients had systemic inflammatory response syndrome, 53% had sepsis, and 5% developed sepsis during their stay in the ICU. Calcitonin precursors, C-reactive protein, interleukin-6, and lactate levels increased with the severity of infection (p < .01, one-way analysis of variance). In a receiver operating characteristic curve analysis, calcitonin precursors were found to be the most reliable laboratory variable for the diagnosis of sepsis as compared with C-reactive protein, interleukin-6, and lactate (p < .01, for each comparison). Calcitonin precursor concentrations of > 1 ng/mL had sensitivity of 89% and specificity of 94% for the diagnosis of sepsis. High serum concentrations of calcitonin precursors were associated with poor prognosis (p = .01).In a medical ICU, serum calcitonin precursor concentrations are more sensitive and are specific markers of sepsis as compared with serum C-reactive protein, interleukin-6, and lactate levels.