We performed a multicenter, historical-cohort analysis to identify factors associated with chronic lung disease (CLD) in extremely low birth weight infants. The 235 infants who were born in 1984 with birth weights of 751 to 1000 gm and admitted to any of 10 participating neonatal intensive care units comprised the study population. We analyzed demographic characteristics, status at birth, severity of acute atelectasis, and early respiratory treatment in relation to CLD, which we defined as having received oxygen at age 30 days. By univariate analysis, CLD was associated with lower gestational age (p less than 0.001), male sex (p = 0.004), more severe acute atelectasis as indicated by a higher roentgenographic score (p less than 0.001), a higher ventilation rate at 96 hours (p = 0.012), and lower PaCO2 at 48 hours (p = 0.04). Infants receiving mechanical ventilation whose highest PaCO2 levels at 48 or 96 hour were less than 40 mm Hg were 1.45 times as likely to develop CLD as those whose highest PaCO2 levels were greater than 50 mm Hg (95% confidence interval 1.04 to 2.01). CLD rates by center were inversely related to mean PaCO2 levels in infants receiving mechanical ventilation at 48 and 96 hours (Spearman rank correlations 0.60 and 0.55; p less than 0.001). A logistic risk model that included sex, PaCO2 at 48 hours, roentgenographic score, gestational age, and race showed only male sex (p = 0.009) and lower PaCO2 at 48 hours (p = 0.04) to be independent predictors of CLD. We conclude that mechanical ventilation that results in PaCO2 levels above the physiologic range may decrease the risk of CLD in extremely low birth weight infants.