Near-infrared spectroscopy is a noninvasive monitoring technique that allows quantitative measurement of changes in cerebral oxygenated Hb (HbO(2)), deoxygenated Hb (Hb), total Hb, and oxidized cytochrome aa(3) (CytO(2)). Changes in cerebral Hb oxygenation and CytO(2) have been measured in human neonates and infants under a variety of conditions. However, the association of these measurements with cerebral high-energy phosphate loss is not known. We studied simultaneous changes in cerebral HbO(2), Hb, total Hb, and CytO(2) by near-infrared spectroscopy and changes in nucleoside triphosphate (NTP, mostly ATP) and phosphocreatine (PC) concentrations and intracellular pH by in vivo P-31-labeled magnetic resonance spectroscopy. Four-wk-old piglets (n = 8) underwent sequential hypoxic episodes of increasing severity (inspired O-2 concentration, 12, 8, 6, 4, and 0%). Animals were anesthetized and mechanically ventilated. At all levels of hypoxia, cerebral HbO(2) decreased, and Hb increased. Loss of PC or NTP was not observed until inspired O-2 concentration was decreased to less than 12%. With such severe hypoxia, hypotension, intracellular acidosis, and increasingly severe PC and NTP depletions occurred. Decreases in PC and NTP correlated closely with decreased CytO(2) and arterial blood pressure (p < 0.0001) but not with changes in HbO(2) and Hb. In conclusion, cerebral hypoxemia is readily detected by near-infrared spectroscopy as a decrease in HbO(2) and an increase in Hb. However, relative changes in cerebral HbO(2) and Hb have low predictive value for cerebral energy failure. Reduction of CytO(2) is highly correlated with decreased brain energy state and may indicate impending cellular injury.