BACKGROUND: Morbidly obese patients with respiratory failure who do not improve on conventional mechanical ventilation (CMV) often undergo rescue therapy with extracorporeal membrane oxygenation (ECMO). We describe our experience with high-frequency percussive ventilation (HFPV) as a rescue modality. METHODS: In a retrospective analysis from 2009 to 2016, 12 morbidly obese patients underwent HFPV after failing to wean from CMV. Data were collected regarding demographics, cause of respiratory failure, ventilation settings, and hospital course outcomes. Our end point data were pre- and post-HFPV partial pressure of arterial oxygen and PaO2 to fraction of inspired oxygen (PF) ratios measured at initiation, 2, and 24 hours. RESULTS: Twelve morbidly obese patients required HFPV for respiratory failure. Causes of respiratory failure overlapped and included cardiogenic pulmonary edema (n = 8), pneumonia (n = 5), septic shock (n = 5), and asthma (n = 1). After HFPV initiation, mean fraction of inspired oxygen FiO2 was tapered from 98% to 82% and 66% at 2 and 24 hours, respectively. Mean PaO2 increased from 60.9 mm Hg before HFPV to 175.1 mm Hg (P < .05) at initiation of HFPV, then sustained at 129.5 mm Hg (P < .05) and 88.1 mm Hg (P < .005) at 2 and 24 hours, respectively. Mean PF ratio improved from 66.1 before HFPV to 180.3 (P < .05), 181.0 (P < .05) and 148.9 (P < .0005) at initiation, 2, and 24 hours, respectively. The improvement in mean PaO2 and PF ratios was durable at 24 hours whether or not the patient was returned to CMV (n = 10) or remained on HFPV (n = 2). Survival to discharge was 66.7%. CONCLUSION: In our cohort of morbidly obese patients, HFPV was successfully utilized as a rescue therapy precluding the need for ECMO. Despite our small sample size, HFPV should be considered as a rescue therapy in morbidly obese patients failing CMV prior to the initiation of ECMO. Our retrospective analysis supports consideration for HFPV as another form of rescue therapy for obese patients with refractory hypoxemia and respiratory failure who are not improving with CMV.