Both exogenous surfactant therapy and high-frequency oscillation (HFO) have been proposed as clinical interventions in acute respiratory distress syndrome (ARDS). The combination of these 2 interventions has not been studied in a relevant model of ARDS. It was hypothesized that surfactant treatment combined with HFO is superior to either surfactant treatment or HFO alone in a model of ARDS. Adult rats had lung injury induced by instillation of 0.1 mol/L HCl, followed by randomization to one of 4 groups: Conventional mechanical ventilation (CMV) + air (no treatment), CMV + surfactant, HFO + air, and HFO + surfactant. Oxygenation, lung compliance, surfactant, and cytokine concentrations in the lung lavage were analyzed. The results showed superior oxygenation in HFO ventilated animals regardless of surfactant treatment compared with CMV. Nonsurfactant-treated animals ventilated with HFO had a significantly greater proportion of large aggregates, and had greater lung compliance compared with non-surfactant-treated animals ventilated with CMV. Surfactant therapy combined with HFO provided no advantages with respect to these outcomes. These data suggest an advantage of HFO over CMV when exogenous surfactant was not given, and that surfactant treatment combined with HFO was not superior to HFO ventilation alone.