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<h3>Introduction</h3> High frequency oscillatory ventilation (HFOV) is as a rescue mode of ventilation however, it did not show benefit in many cases. <h3>Objectives</h3> To identify which patient are best treated with HFOV and which ones will not improve or deteriorate, and the best way of selection and adjustment of HFOV settings in the first 48 hours. <b>Study Design:</b> Retrospective observational study. <b>Settings:</b> One tertiary level PICU. <b>Subjects:</b> 207 patients under 18 years who were admitted to PICU with respiratory failure and switched to (HFOV) in the period between September 2010 till December 2017. <b>Intervention:</b> None <h3>Results</h3> HFOV was used 241 times. 34 cases were excluded and 207 HFOV episodes were analyzed. The median age was 12 (4, 48 IQR) months with 52.7% males. Etiology of respiratory failure was classified as diffuse alveolar disease (DAD) and small airway disease (SAD). The most common cause of respiratory failure was ARDS, 100 (48%) cases then pneumonia, 34 (16.4%) cases, two cases of asthma and 8 with bronchiolitis. Majority had an underlying chronic illness (87.4%). Oxygenation failure was the most common reason for HFOV (77.3%). Over the first 48 hours there was a significant improvement in oxygenation but faster in ventilation and acid base status. Variables that were associated with 48 hours mortality were shorter duration of CMV, lower pH, not using NMB agents, sepsis, high vasopressor index and hypotension just before switching to or within the 48 hours of HFOV. 48 hours mortality was significantly higher in patients with hematological malignancies (OR 8.73 (1.58–48.06), <i>p</i> = 0.013 and in the poorly identified group that did not fit into DAD or SAD categories when compared with ARDS (OR 2.73 (1.13–6.58), <i>p</i> = 0.030). Conventional ventilation settings were not statistically significant between surviving vs non-surviving groups (<i>p</i> > 0.05). <h3>Conclusion</h3> HFOV has a great value in improving oxygenation and ventilation when conventional mode fails. The underlying disease seems to have a significant impact on the outcome and immune function and malignancies are the main categories. Hemodynamic instability and sepsis are major contributors to worse short-term outcome.