The cerebral fractional oxygen extraction (FOE) reflects the balance between cerebral oxygen delivery (OD) and consumption (VO(2)). PCO(2) affects the cerebral blood flow (CBF): hypocapnia decreases CBF and OD and increases FOE. We recently showed that the fractional tissue oxygen extraction (FTOE) reflects FOE and hypothesized that a decrease in tPCO(2) increases FTOE. In this study we looked at the effect of changes in tPCO(2) on FTOE. We analysed 23 measurements in 13 neonates with birth weight below 1500 g and need for intensive care. Exclusion criteria were congenital malformations or cerebral complications. The tissue oxygenation index (TOI), tPCO(2), mean arterial blood pressure (MABP), heart rate (HR) and peripheral oxygen saturation (SaO(2)) were continuously recorded for 4h during the first days of life and FTOE was calculated. Over the whole group we found a significant negative (r=-0.227) correlation between tPCO(2) and FTOE and a significant positive (r=0.258) correlation between tPCO(2) and TOI. After correction for MABP these correlations remained significant. Over the whole group we found a significant positive correlation between tPCO(2) and TOI and a significant negative correlation between tPCO(2) and FTOE, which remained significant after correction for MABP. This implies that tPCO(2) influences the cerebral oxygenation independently of MABP. We therefore believe that for the interpretation of cerebral oxygenation in mechanically ventilated neonates during the first days of life continuous measurements of tPCO(2) are needed. Moreover we suggest FTOE to become a continuous parameter in the clinical setting for the non-invasive measurement of the neonatal brain oxygenation.