Several etiologies for causing periventricular leukomalacia (PVL) in preterm infants have been investigated worldwidely. The aim of this study is to investigate whether hypocapnia plays a role in the pathogenesis of the subsequent development of PVL. From Jan. 1997 to June 1998, 91 premature infants (mean gestational age 28.8 +/- 2.5 weeks and birth body weight 1169 +/- 385 g) born in Chung Gung Children's Hospital requiring mechanical ventilation in the first 72 hrs were enrolled in our study. Serial neuorosonogram were followed on day 1, 3, 7 and then at least every 2 to 3 weeks until discharge. These infants were divided into two groups defined as the PVL group and non-PVL group. Variables comprising perinatal data were analyzed and compared between these two groups to screen out possible risk factors related to the development of PVL. There was no difference noted. As for the effect of PaCO2, we found the infants with PVL to have mean lower PaCO2 during the first 72 hours of life. (P = 0.004). Logistic regression model revealed that the incidence for PVL increased significantly when mean PaCO2 is lowered to less than 25 mmHg. Hypocapnia during the first three days of life seems to be an important etiological factor associated with the development of periventricular leukomalacia. Therefore, the ventilatory strategy in the care of the premature neonates should not only provide adequate ventilation but also careful avoidance of hypocapnia.