Among 315 infants treated for respiratory distress syndrome (RDS) over a 2 year period, 32 prematures were studied retrospectively with the diagnosis of pulmonary interstitial emphysema (PIE). Eighteen died. In this group, birth weight below 1600 g, need for oxygen above 0.6 on the 1st day and appearance of bilateral pulmonary interstitial emphysema within the first 48 h of life were significant risk factors, with a mortality rate of 94%. In order to recognize one or more early criteria predictive of fatal PIE, we compared ventilation parameters on day 1 between neonates with fatal PIE and those with the same birth weight and initial severity of RDS but without PIE treated during the same period. High positive inspiratory pressure on day 1 was found to be the most significant parameter associated with further appearance of fatal pulmonary interstitial emphysema. A cut-off level of 26 cm H2O was found to be discriminant. These criteria may be useful in selecting those neonates who might best benefit from a new therapy such as high frequency ventilation, before irreversible lesions appear.