Oxidative damage to surfactant can decrease lung function in vivo. In the current study our two objectives were: 1) to examine if the adverse effects of oxidized surfactant would be accentuated in animals that were exposed to high tidal volume ventilation and 2) to test if supplementation with surfactant protein A (SP-A) could improve the function of oxidized surfactant in vivo. The first objective was addressed by evaluating the response of surfactant deficient rats that were administered normal or oxidized surfactant and then subjected to low tidal volume (6ml/kg) or high tidal volume (12ml/kg) mechanical ventilation. Under low tidal volume conditions, rats administered oxidized surfactant had impaired lung function, as determined by lung compliance and arterial blood gas analysis, compared to the non oxidized controls. Animals that were subjected to the high tidal volume ventilation had impaired lung function compared to the low tidal volume groups, regardless of the oxidative status of the surfactant. The second experiment demonstrated a significantly superior physiologic response in surfactant deficient rats receiving SP-A containing oxidized surfactant compared to oxidized surfactant. Lavage analysis after ventilation showed no differences in the recovery of oxidized surfactant compared to non oxidized surfactant. It is concluded that minimizing excessive lung stretch during mechanical ventilation is important in the context of exogenous surfactant supplementation and that SP-A has an important biophysical role in surfactant function in conditions of oxidative stress. Furthermore, the oxidative status of the surfactant does not appear to affect the alveolar metabolism of this material.