One hundred twenty preterm newborns less than 34 weeks' gestational age have been studied prospectively to determine the frequency of fetal and newborn metabolic acidosis and to examine the relationship of metabolic acidosis to periventricular leukomalacia as demonstrated by serial newborn ultrasonographic examinations. Fetal metabolic acidosis, based on an umbilical artery buffer base less than 34 mmol/L at delivery, occurred in three cases (2%), one of which had evidence of periventricular leukomalacia. Newborn metabolic acidosis that is based on a buffer base less than 34 mmol/L during the 4 days after delivery occurred in 12 cases (10%), five of which had evidence of periventricular leukomalacia. There is a significant relationship between the degree and duration of newborn metabolic acidosis and the occurrence of periventricular leukomalacia. This study indicates that systemic metabolic acidosis is an important pathophysiologic marker of periventricular leukomalacia. Intrapartum fetal asphyxia with metabolic acidosis, although an infrequent occurrence in the preterm newborn, may account for a few cases of periventricular leukomalacia, while the more common newborn metabolic acidosis, when of sufficient degree and duration, carries a high risk of periventricular leukomalacia.