Our objective was to determine survival and variables associated with poor outcomes for patients requiring high frequency oscillatory ventilator (HFOV) support. We tested the ability of markers of oxygenation to predict outcome, specifically, the oxygenation index (OI), both prior to and after initiation of HFOV. We also aimed to examine the effect of immunocompromised condition (IC), and specifically stem cell transplant (SCT), on outcome. A retrospective, observational study was performed at two pediatric intensive care units (ICU) and included patients treated with HFOV over a 5 year time period. Oxygenation index and PF ratios were calculated for all patients prior to and at 24 h of HFOV support. Of the 134 patients meeting inclusion criteria, mortality was 42% with a higher rate of mortality (P < 0.001) for both immunocompromised (66%) and SCT patients (83%). Survivors had improved markers of oxygenation at 24 h as compared to non-survivors (P < 0.001). IC and SCT were the variables most closely associated with mortality. Survivors were placed on HFOV earlier than non-survivors. The OI at 24 h of HFOV support was the best predictor of mortality among markers of oxygenation. In this cohort of patients, use of HFOV for pediatric respiratory failure demonstrated a mortality rate in keeping with published data. The presence of an immunocompromised condition was a risk factor for mortality in severe respiratory failure with SCT recipients having the lowest survival rate. The OI at 24 h was the best predictor of mortality, especially in immunocompromised and SCT patients.