Case reports of all infants admitted to the NICU from 1971 to 1982, who developed a pneumopericardium (PPC) while receiving intermittent positive-pressure ventilation, were reviewed in order to determine those variables of assisted ventilation associated with the occurrence of PPC. Of 19 infants seen during the 11-yr period, 16 had respiratory distress syndrome (RDS) and 3 had other forms of severe pulmonary disease. Mean birth weight was 1720 g, gestational age 32 wk, and age at occurrence 59 h. Peak inspiratory pressure (PIP) (mean 32 cm H2O), inspiratory time (IT) (0.74 sec), and mean airway pressure (MAP) (mean 17 cm H2O) were significantly elevated just before occurrence of the PPC, compared with values 6 h previously. PEEP (mean 3.8 cm H2O), ventilator rate (mean 40/min), PaCO2 (mean 41 torr), P(A-a)O2 (mean 443 torr), and inspired oxygen concentration (FIO2, 0.77) were unchanged. MAP was significantly lower (mean 11 cm H2O) 6 h after the event compared with just before (mean 14 cm H2O) in infants who died, suggesting that lowering airway pressure does not improve survival. These data indicate that high PIP, prolonged IT and elevated MAP are associated with the development of PPC. MAP provides a composite of pressure transmitted to the airways and may be the more useful index in preventing barotrauma and pulmonary air leak.