Background: Very low birthweight (VLBW) premature infants (BW< 1500 grams) are at high risk for developing severe intracranial hemorrhage (Gr 3 and 4 IVH). We have enrolled a large number of VLBW infants into a series of federally-funded trials assessing the risk factors associated with brain injury. The objective of this investigation was to assess the role of hypercapnia in the development of Gr 3 and 4 IVH in VLBW infants born during both the pre-surfactant and surfactant eras. Methods: Infants were enrolled during two periods of time: 1981-1989 (pre-surfactant use) and 1991-1995 (all received surfactant). Inclusion criteria included: 1) GA ≤ 32 weeks; 2) BW < 1500 grams; 3) requirement for conventional mechanical ventilation; and 4) enrollment at < 24 hours of age. Exclusion criteria included: 1) single or multiple congenital anomalies; 2) no parental consent; 3) any use of other than conventional mechanical ventilation (eg. high frequency or liquid ventilation); or 4) nonviability due to the degree of immaturity. Comprehensive prenatal, birth-related, and postnatal data were collected. All ventilator settings and arterial blood gas data were recorded. Serial neurosonograms were performed during the first 72 hours of life and weekly therafter. We assessed the ventilator settings, arterial blood gases, and neurosonogram results during the first 72 hours of life. Additionally, we evaluated multiple other factors which could potentially influence the development of IVH. Results: Of 227 VLBW infants enrolled during the presurfactant era, 38 (17%) developed Grade 3 or 4 IVH. The single highest PaCO2 recorded during the first 72 hours was significantly higher in the 38 infants with Grade 3 or 4 IVH (median 50 vs. 45, respectively; P=0.016). Of 97 VLBW neonates enrolled during the surfactant era, 24 (24%) developed Grade 3 or 4 IVH. The single highest PaCO2 recorded during the first 72 hours in the latter group was also significantly higher in the infants with Grade 3 or 4 IVH (median 54 vs. 47, respectively; P=0.023). Conclusions: Hypercapnia may play a role in the development of severe intracranial bleeding in VLBW premature infants. Until prospective, controlled trials are completed, caution should be used before adopting a policy of permissive hypercapnia in such infants.