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The role of CD64 in late onset sepsis (LOS) in preterm infants has been described in several studies. Aim of this study was to investigate whether CD64 expression is increased in the days before clinical manifestation of LOS.Patients with birth weight below 1,500 g were eligible for study participation. During routine blood sampling CD64 index was determined between day of life 4 and 28. Patients were allocated to one of four groups: (1) blood-culture positive sepsis, (2) clinical sepsis, (3) symptoms of infection without biochemical evidence of infection, or (4) patients without suspected infection. Kinetics of CD64 expression were compared during a period before and after the day of infection in the respective groups.50 infants were prospectively enrolled and allocated to each group as follows: group (1) n = 7; group (2) n = 10; group (3) n = 8; and group (4) n = 25. CD64 index was elevated in 57% of patients in group (1) at least two days before infection. In contrast only 20% in the clinical sepsis group and 0% in group (3) had an elevated CD64 index in the days before infection. 10 of the 25 patients in the control group (4) presented increased CD64 index values during the study period.The CD64 index might be a promising marker to detect LOS before infants demonstrate signs or symptoms of infection. However, larger prospective studies are needed to define optimal cut-off values and to investigate the role of non-infectious inflammation in this patient group.