Thirteen premature infants receiving mechanical ventilation for respiratory distress syndrome developed pneumopericardium. All had high peak inflation pressures (mean, 42 mm Hg; range, 26 to 60 mm Hg), and all were on positive end-expiratory pressure (PEEP) ventilation (mean, 3.1 mm Hg; range, 2.1 to 5.7 mm Hg) at the time that pneumopericardium occurred. Arterial blood gases, indices of respiratory support, and hemodynamic data were reviewed before and after the onset of pneumopericardium in all patients. There was a statistically significant increase in peak inflation pressure (PIP) over the 16 hours prior to onset of pneumopericardium (p less than 0.05). There was, however, no significant relationship between onset of pneumopericardium and other respiratory variables, including PEEP. In the majority of patients, pneumopericardium was associated with cardiac air tamponade. Various forms of treatment for pneumopericardium were attempted, including observation, needle aspiration, and insertion of pericardial tubes. Review of the therapy indicates that insertion of a pericardial tube under direct vision is the safest and most effective means of treating pneumopericardium in infants. These data also suggest that PIP is more important than PEEP in predisposing neonates with respiratory distress syndrome to pneumopericardium.