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C-reactive protein (CRP) is a nonspecific, acute-phase protein that rises in response to infectious and noninfectious inflammatory processes. Good evidence exists to support the use of CRP measurements in conjunction with other established diagnostic tests (such as a white blood cell (WBC) count with differential and blood culture) to establish or exclude the diagnosis of sepsis in full-term or near-term infants.This article reviews the immunologic function of CRP and the history of CRP testing. The 3 methods for measuring CRP and the sensitivity and specificity of this diagnostic test are analyzed. Guidelines for the use of CRP in the evaluation and management of infants with suspected sepsis are presented.Quantitative serial CRP levels, obtained 24 hours after the onset of signs and symptoms of infection, with serial measurements 12 to 24 hours apart, offer the most sensitive and reliable information. At least 2 CRP levels, obtained 24 hours apart, with levels ≤10 mg/L, are needed to identify infants unlikely to be infected. The use of CRP to exclude infection may allow clinicians to discontinue antibiotics at 48 hours in select infants, limiting extended unnecessary antibiotic exposure.