Pneumopericardium, a complication of ventilatory management of neonatal respiratory distress syndrome, may result in cardiac tamponade. Pneumopericardium occurred in 47 premature infants (mean birth weight, 1,894 gm) at the University of Minnesota Hospital between July, 1972, and January, 1981. At the onset of pneumopericardium, 44 of 46 intubated patients were on positive end-expiratory pressure (PEEP) and 1 patient was ventilated using a mask. Five infants were asymptomatic, while 42 were seen with sudden hypotension, bradycardia, and hypoxia an average of 57 hours (range, 1 to 312 hours) after the commencement of ventilatory support. Pneumothorax (38 instances), pneumomediastinum (21), pulmonary interstitial emphysema (29), pneumoperitoneum (6), or a combination of these conditions was noted prior to or simultaneously with pneumopericardium in 46 infants. Pneumopericardium was not treated in 14 patients, 10 of whom were symptomatic and 4 asymptomatic; there were 5 deaths in this group. The group of 33 infants treated for this complication underwent either pericardial aspiration (2 patients), aspiration followed by pericardial tube placement (12 patients), or pericardial tube placement alone (19 patients). All 33 patients who underwent treatment had resolution of symptoms, but pneumopericardium recurred in 13 with 5 deaths. Causes of recurrence were tube or aspiration failure in 10 infants and tube removal prior to cessation of PEEP in the other 3. There were five complications related to tube placement, resulting in 2 deaths due to myocardial laceration following percutaneous insertion. Of 35 neonates surviving pneumopericardium, 12 were discharged from the hospital and 23 died of complications of respiratory distress syndrome. Pneumopericardium should be treated initially by emergency pericardial aspiration to relieve symptoms of tamponade and then by placement of an anterior pericardial tube under direct vision. The tube should remain in place until PEEP is discontinued.