Phenobarbital (PB), at anticonvulsant dosages, has been used in an attempt to reduce hypoxic brain injury in asphyxiated newborn infants. The effects of PB pretreatment on the cerebral blood flow (CBF) response in hypoxia were studied in 15 curarized and mechanically ventilated piglets: 7 animals were pretreated with 20 mg/kg of PB (group 1) and 8 served as untreated controls (group 2). Successive aliquots (25 ml) of carbon monoxide were introduced into a closed ventilator circuit and CBF (measured with radiolabelled microspheres), arterial blood pressure, blood gases, arterial pH and PaO2 were subsequently determined at different levels of hypoxia. The amount of hemoglobin available for oxygen transport (i.e. total Hb-HbCO) was used to express hypoxic aggression and decreased from grade I (> 2 mmol/l) to grade II (1-2 mmol/l) to grade III (< 1 mmol/l). In the control group, CBF increased during grade-I hypoxia and continuously remained above baseline values during grade-II and grade-III hypoxia. In pretreated animals, however, only grade-II hypoxia was associated with a significant increase in CBF above baseline. In addition during grade-III hypoxia, CBF decreased to the prehypoxic values despite a fall in cerebral oxygen delivery and cardiac index. These data suggest that PB should be used with caution to prevent brain damage in the asphyxiated newborn infants.