Updated project metadata. Staphylococcus (S.) epidermidis is one of the most common nosocomial coagulase-negative staphylococci infections in preterm infants. The clinical signs of infection are often unspecific and identification of novel markers to complement the current diagnosis is needed. In this study, we investigated proteomic alterations in the neonatal mouse brain following S. epidermidis infection and in the blood in preterm infants. We identified lipocalin 2 (LCN2) as a crucial protein associated with cerebrovascular changes and astrocyte reactivity in mice. While astrocytes were activated in S. epidermidis infected mice, LCN2 protein expression in the brain was associated with endothelial cells but not astrocyte reactivity. By combining weighted gene co-expression analysis and differential expression approaches, we further identified that LCN2 protein was linked to blood C-reactive protein levels in a cohort of preterm infants born <28 weeks of gestation. Blood LCN2 levels were associated with similar alterations of cytokines and chemokines in both infected mice and human preterm infants with increased levels of CRP. The present experimental and clinical study indicates that LCN2 might be a suitable additional marker of preterm infection/inflammation associated with cerebrovascular changes and neuroinflammation.