The objectives of this study were to measure the effect of acetazolamide on cerebral circulation, pulmonary elimination of CO2, and cerebrovascular response to hypotension in newborn piglets. Eighteen anaesthetized newborn piglets were studied. A fontanelle was surgically created and the cerebral blood flow velocity (CBFV) in an intracranial artery measured by a computerized Doppler system. In 8 piglets, 30 ml/kg of blood was removed to produce hypotension before the administration of acetazolamide. Acetazolamide (50 mg/kg i.v.) given to normotensive piglets consistently produced a large increase in CBFV (median 45% by 5 min) with no change in mean arterial blood pressure or heart rate. The rise in CBFV was negatively correlated with the starting partial pressure of CO2 in arterial blood. Within 1 min of administration of acetazolamide, the end-expiratory CO2 pressure started to fall (mean fall 1.4 kPa), and the partial pressure of CO2 in the arterial blood started to rise (mean rise 2.0 kPa), despite the controlled ventilation being unchanged. Acetazolamide had no effect on CBFV in the hypotensive piglet. It seems likely that acetazolamide produces cerebral vasodilatation by inhibiting the elimination of CO2. In hypotension, there is maximal cerebral vasodilatation, and acetazolamide cannot increase CBFV further. The interference of acetazolamide with CO2 elimination could seriously limit its use in the treatment of hydrocephalus in preterm infants.