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Introduction: Sepsis is a systemic inflammatory response to suspected or confirmed infection. Clinical evaluations are essential for its early detection and treatment. Blood cultures may take as long as 2 days to yield a result and are not always reliable. However, recent studies have suggested that neutrophil CD64 expression may be a sensitive and specific alternative for the diagnosis of systemic infection. Objective: The objective of the study was to analyze the difference in CD64 values between subjects with systemic inflammatory response syndrome (SIRS), suspected or confirmed sepsis, who meet diagnostic criteria for SIRS upon arriving at an emergency department. Materials and Methods: This was a prospective observational cohort study, an accuracy study of CD64 prospectively evaluated. The sample consisted of 109 patients aged 18 years with criteria for SIRS on arrival to emergency department. CD64 expression was measured within 6 h of hospital admission and once again after 48 h. Results: ROC curve analysis suggested that a cutoff of 1.45 for CD64 expression could diagnose sepsis with a sensitivity of 0.85, a specificity of 0.75, an accuracy of 82.08%, a positive predictive value of 0.96, a negative predictive value of 0.38 and a positive likelihood ratio of 3.33. The area under the curve was 0.83. Conclusion: CD64 seems to be a useful, sensitive, and specific biomarker in discriminating between SIRS and sepsis.