Sepsis continues to be a significant source of morbidity and mortality in the neonatal intensive unit. At the same time, we need to contain medical costs and prevent the rapid growth of resistant organisms by limiting unnecessary antibiotic use. Among laboratory indexes studied as indirect indicators of the presence and resolution of infection and inflammation, C-reactive protein (CRP) has gained more recent widespread use. CRP usually increases in a delayed manner with the onset of inflammation and decreases as inflammation resolves. We follow serial CRP values in our neonatal intensive care unit from the start of a sepsis evaluation until antibiotic therapy is withdrawn. We describe two extremely low birth weight patients who improved clinically with therapy and whose CRP levels normalized in the face of continued positive blood cultures. The implications for the use of CRP in deciding when to halt therapy in premature infants are discussed.