The present study tests the hypothesis that ventilation with 100% O 2 during recovery from asphyxia leads to greater disturbance in brain function, as measured by dopamine metabolism, than does ventilation with 21% oxygen. This hypothesis was tested using mechanically ventilated, anesthetized newborn piglets as an animal model. Cortical oxygen pressure was measured by the oxygen-dependent quenching of phosphorescence, striatal blood flow by laser Doppler, and the extracellular levels of dopamine and its metabolites by in vivo microdialysis. After establishment of a baseline, both the fraction of inspired oxygen (F I o 2 ) and the ventilator rate were reduced in a stepwise fashion every 20 min over a 1-h period. For the subsequent 2-h recovery, the animals were randomized to breathing 21 or 100% oxygen. It was observed that during asphyxia cortical oxygen pressure decreased from 36 to 7 torr, extracellular dopamine increased 8,300%, and dihydroxyphenylacetic acid and homovanillic acid decreased by 65 and 60%, respectively, compared with controls. During reoxygenation after asphyxia, cortical oxygen pressure was significantly higher in the piglets ventilated with 100% oxygen than in those ventilated with 21% oxygen (19 vs. 11 torr). During the first hour of reoxygenation, extracellular dopamine levels decreased to ∼ 200% of control in the 21% oxygen group, whereas these levels were still much higher in the 100% oxygen group (∼ 500% of control). After ∼ 2 h of reoxygenation, there was a secondary increase in extracellular dopamine to ∼ 750 and ∼ 3,000% of baseline for the animals ventilated with 21 and 100%, respectively. It is concluded that although 100% F I o 2 after asphyxia increases cortical oxygenation compared with 21% F I o 2 , it also results in poorer recovery in dopamine metabolism and higher secondary release of striatal dopamine. The resulting increased extracellular levels of dopamine may exacerbate posthypoxic cerebral injury.