The reaction of cerebral blood flow to acute changes in arterial carbon dioxide pressure (PaCO2) and mean arterial blood pressure was determined in 57 preterm infants supported by mechanical ventilation (mean gestational age 30.1 weeks) during the first 48 hours of life. All infants had normal brain sonograms at the time of the investigation. In each infant, global cerebral blood flow was determined by xenon-133 clearance two to five times within a few hours at different levels of PaCO2. Changes in PaCO2 followed adjustments of the ventilator settings. Arterial oxygen pressure was intended to be kept constant, and mean arterial blood pressure fluctuated spontaneously between measurements. The data were analyzed by stepwise multiple regression, with changes in global cerebral blood flow, PaCO2, mean arterial blood pressure, and postnatal age or intracranial hemorrhage used as variables. In infants with persistently normal brain sonograms, the global cerebral blood flow-carbon dioxide reactivity was markedly lower during the first day of life (mean 11.2% to 11.8%/kPa PaCO2) compared with the second day of life (mean 32.6/kPa PaCO2), and pressure-flow autoregulation was preserved. Similarly, global cerebral blood flow-carbon dioxide reactivity and pressure-flow autoregulation were present in infants in whom mild intracranial hemorrhage developed after the study. In contrast, global cerebral blood flow reactivity to changes in PaCO2 and mean arterial blood pressure was absent in infants in whom ultrasonographic signs of severe intracranial hemorrhage subsequently developed. These infants also had about 20% lower global cerebral blood flow before hemorrhage, in comparison with infants whose sonograms were normal, a finding that suggests functional disturbances of cerebral blood flow regulation. Several perinatal factors were tested, but only birth after abruptio placentae was related to subsequent periventricular hemorrhage (p = 0.037).