The objective of this study was to compare the effect of extracorporeal membrane oxygenation (ECMO) on cerebral oxygenation and hemodynamics in normoxemic and hypoxemic piglets. Six hypoxemic and six normoxemic piglets were put on venoarterial ECMO after cannulation of the right common carotid artery and external jugular vein with careful priming to avoid hemodilution. Changes in cerebral concentrations of oxyhemoglobin (cO2Hb), deoxyhemoglobin (cHHb), (oxidized-reduced) cytochrome aa3 (cCyt.aa3), and blood volume (CBV) were continuously measured by near infrared spectrophotometry. Heart rate, arterial O2 saturation (SaO2), arterial blood pressure, pulsatility ratio of systemic circulation (calculated as systolic-diastolic/mean arterial blood pressure), central venous pressure, intracranial pressure, and left common carotid artery blood flow (LCaBF) were simultaneously measured. We found that the cannulation procedure resulted in increased CBV, cHHb, and LCaBF in both groups. At 60 and 120 min after starting ECMO, the values of cO2Hb, CBV, and LCaBF in both groups were significantly higher than precannulation values, while the pulsatility ratio decreased. In the hypoxemic groups cHHb decreased and SaO2 increased as well. No significant changes of other variables were found. Between hypoxemic and normoxemic groups no significant differences in the response of CBV and LCaBF at 60 and 120 min were found. We conclude that in piglets cannulation for ECMO resulted in cerebral venous congestion and compensated increase in LCaBF. After starting ECMO, the cerebral O2 supply increased due to increased arterial O2 content. It was accompanied by similar increase of CBV in both groups, probably as a result of hyperperfusion, which seems to be related to the ECMO procedure itself.