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Objective Neonates with sepsis have increased risk of cerebral injury. Our aim was to evaluate cerebral oxygenation in septic neonates using near-infrared spectroscopy. Study Design A prospective study was designed enrolling neonates with sepsis, as defined by the International Consensus Conference of Pediatric Sepsis criteria and matched controls. Three cerebral half-hourly measurements were performed during the first, third, and seventh day of the episode and the values of tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were compared between the two groups. Result The study population consisted of 50 septic and 44 control neonates with similar characteristics. No differences on TOI and FTOE were recorded in the first and third day. However, on the seventh day, septic neonates had significantly decreased oxygenation (62.7 ± 7 vs. 71.4 ± 4.4%, p < 0.001) and increased oxygen extraction (0.35 ± 0.07 vs. 0.27 ± 0.05, p < 0.001), irrespectively of the severity of the infection. Conclusion Although septic neonates have normal cerebral oxygenation in the first and third day of the sepsis, they present decreased cerebral oxygenation in the seventh day independently of the infection severity. [ABSTRACT FROM AUTHOR]