We investigated the effect of a two-way exchange transfusion on cerebral hemodynamics and oxygenation in 3 neonates using near infrared spectroscopy (NIBS). A total of 4 exchange transfusions (ET) for the treatment of sepsis were performed. Cerebral oxyhemoglobin concentrations (HbO₂) increased immediately after commencing with ET by 8.82±3.46 (mean±SD)μmol/l, which persisted throughout the ET. Total hemoglobin concentrations (HbT) simultaneously increased by 8.92±3.81 (mean±SD)μmol/l. No changes in cerebral deoxyhemoglobin concentrations (HbR) and cytochrome aa₃ (Cytaa₃) were observed. In one occasion, however, HbR increased markedly and HbO₂ decreased immediately after ET had begun, thus HbT remained slightly increased compared to the 3 other occasions. The extension of periventricular echogenecity was observed after ET by cranial ultrasound scan in this patient and periventricular leukomalacia was confirmed by autopsy. We conclude that a two-way exchange transfusion increases cerebral blood volume and improves cerebral oxygen delivery. Furthermore NIBS was useful in monitoring changes in cerebral hemodynamics and oxygenation in unstable septic neonates.