The purpose of this study was to evaluate the effectiveness of, and complications associated with High Frequency Oscillatory Ventilation (HFOV) in burn patients with the Acute Respiratory Distress Syndrome (ARDS) who have had a smoke inhalation injury, and to compare with those without an inhalation injury. Burn patients with progressive oxygenation failure from ARDS while on conventional mechanical ventilation were placed on HFOV as a “rescue” ventilation modality. There were 19 patients with burn + inhalation injury and 30 patients with burn only. Burned patients with ARDS but without inhalation injury had significant temporal improvement in the oxygenation index from 27 ± 8 on conventional mechanical ventilation to 17 ± 6 within 48 hours of initiating HFOV. However, burned patients with ARDS and smoke inhalation injury did not achieve significant or even eventual improvements in oxygenation index with HFOV. There was also a trend towards higher rates of early HFOV failure and severe hypercapnia while on HFOV among the patients with inhalation injury. Delivery of nebulized bronchodilators, heparin and n-acetyl cysteine, normally mainstays of smoke inhalation therapy, was impossible during HFOV. The presence of a smoke inhalation injury appears to impair the response to HFOV when this ventilation modality is instituted for ARDS-related oxygenation failure. Severe hypercapnia tended to be more frequent during HFOV among patients with smoke inhalation. These findings, combined with the difficulties in delivery of nebulized medications during HFOV suggest that HFOV may not be the optimal “rescue” ventilation modality in cases of ARDS if there has been an inhalation injury.