Detection of cerebral hypoxia-ischemia remains problematic in neonates. Near-infrared spectroscopy, a noninvasive bedside technology has potential, although thresholds for cerebral hypoxia-ischemia have not been defined. This study determined hypoxic-ischemic thresholds for cerebral oxygen saturation (SCO2) in terms of EEG, brain ATP, and lactate concentrations, and compared these values with CBF and sagittal sinus oxygen saturation (SVO2). Sixty anesthetized piglets were equipped with near-infrared spectroscopy, EEG, laser-Doppler flowmetry, and a sagittal sinus catheter. After baseline, SCO2 levels of less than 20%, 20% to 29%, 30% to 39%, 40% to 49%, 50% to 59%, 60% to 79%, or 80% or greater were recorded for 30 minutes of normoxic normocapnia, hypercapnic hyperoxia, or bilateral carotid occlusion with or without arterial hypoxia. Brain ATP and lactate concentrations were measured biochemically. Logistic and linear regression determined the SCO2, CBF, and SVO2 thresholds for abnormal EEG, ATP, and lactate findings. Baseline SCO2 was 68 + 5%. The SCO2 thresholds for increased lactate, minor and major EEG change, and decreased ATP were 44 +/- 1%, 42 +/- 5%, 37 +/- 1%, and 33 +/- 1%. The SCO2 correlated linearly with SVO2 (r = 0.98) and CBF (r = 0.89), with corresponding SVO2 thresholds of 23%, 20%, 13%, and 8%, and CBF thresholds (% baseline) of 56%, 52%, 42%, and 36%. Thus, cerebral hypoxia-ischemia near-infrared spectroscopy thresholds for functional impairment are SCO2 33% to 44%, a range that is well below baseline SCO2 of 68%, suggesting a buffer between normal and dysfunction that also exists for CBF and SVO2.