The diagnosis of sepsis is often difficult and belated, substantially increasing mortality in affected patients. Its early identification allows for us to choose the most appropriate therapies in the shortest time, improving patients’ outcomes and eventually their survival. Since neutrophil activation is an indicator of an early innate immune response, the aim of the study was to evaluate the role of Neutrophil-Reactive Intensity (NEUT-RI), which is an indicator of their metabolic activity, in the diagnosis of sepsis. Data from 96 patients consecutively admitted to the Intensive Care Unit (ICU) were retrospectively analyzed (46 patients with and 50 without sepsis). Patients with sepsis were further divided between sepsis and septic shock according to the severity of the illness. Patients were subsequently classified according to renal function. For the diagnosis of sepsis, NEUT-RI showed an AUC of >0.80 and a better negative predictive value than Procalcitonin (PCT) and C-reactive protein (CRP) (87.4% vs. 83.9% and 86.6%,p= 0.038). Unlike PCT and CRP, NEUT-RI did not show a significant difference within the “septic” group between patients with normal renal function and those with renal failure (p= 0.739). Similar results were observed among the “non-septic” group (p= 0.182). The increase in NEUT-RI values could be useful in the early ruling-out of sepsis, and it does not appear to be influenced by renal failure. However, NEUT-RI has not proved to be efficient in discriminating the severity of sepsis at the time of admission. Larger, prospective studies are needed to confirm these results.