Abstract The impact of mechanical ventilation with high VT-low PEEP in infant rats with preinjured lungs is unknown. After tracheal instillation of saline or acid, two week old rats were ventilated with VT 7mL/kg and PEEP 5cm H2O or VT 21mL/kg and PEEP 1cm H2O for 4h. Airway resistance and the coefficient of tissue elastance, measured via low-frequency forced-oscillation technique, and quasi-static pressure-volume curves deteriorated less with high VT-low PEEP when compared with low VT-high PEEP. IL-6 concentration in bronchoalveolar lavage fluid (BALF) did not differ between all ventilated groups. Moreover, differences in BALF protein concentration and histological lung injury scores were independent of applied ventilation strategies. In contrast to experimental studies with adult rats, short-term mechanical ventilation with high VT-low PEEP is not deleterious when compared to low VT-high PEEP in both healthy and pre-injured infant rat lungs. Our results call for caution when extrapolating data from adult studies and highlight the need for age-specific animal models.