• We compared the ventilatory requirements of 127 infants who received phenobarbital for five days with those of 111 infants who received placebo. All infants were intubated, weighed less than 1750 g at birth, and survived the first ten days of life. Those infants who received phenobarbital did not require ventilatory assistance for more days than did placebo receivers. However, a pneumothorax or pulmonary interstitial emphysema was more likely to develop in infants who received phenobarbital than in infants who received placebo, even when adjustment was made for the presence of subependymal-intraventricular hemorrhage. We believe this is the first report of this relationship and recommend additional studies to test the hypothesis that phenobarbital contributes to the occurrence/recognition of pneumothorax or pulmonary interstitial emphysema in very-low-birth-weight infants if phenobarbital continues to be used routinely as prophylaxis or treatment.