Changing lung dynamics and ventilator settings were studied prospectively from onset of respiratory distress syndrome in 32 very low birthweight infants (790-1,460 g, mean 1,173 g). Infants were studied in the first and second week of life using pneumotachography for dynamic compliance and lung resistance calculated from spontaneous breaths. Infants were ventilated to maintain pH at or above 7.30, PCO2 40-50 torr, and PO2 50-70 torr. Eleven infants developed chronic lung disease (CLD). In the first week, CLD infants had lower compliance (0.87 vs. 1.01 mL/cm H2O) and higher resistance (94.23 vs. 76.29 cm H2O/L/sec) than non-CLD infants. CLD infants required greater mean airway pressure (9.56 vs. 7.02 cm H2O; P = .05) and higher peak inspiratory pressures (21.85 vs. 15.71 cm H2O; P = .01). Oxygen requirements were greater for CLD infants (FIO2 0.59 vs. 0.45, P = .05). During the second week compliance for CLD infants improved (1.00) and resistance decreased slightly (92.23), but peak inspiratory pressure settings remained higher for CLD infants (19.60 vs. 14.95 cm H2O; P = .02). Although pulmonary mechanics remained stable for both groups, infants exposed to continuously greater peak inspiratory pressure and oxygen concentration proved susceptible to CLD. Developing a match of ventilator settings to improve pulmonary mechanics may lessen CLD of infancy.