OBJECTIVE To identify clinical factors in term neonates with severe respiratory failure that predict which neonates are unlikely to respond to high-frequency oscillatory ventilation (HFOV). METHODS This was a retrospective review of patient charts and medical records. METHODS We studied 190 newborns treated with HFOV between July 1985 and December 1992. All patients were at least 35 weeks' estimated gestational age and had severe respiratory failure, defined as arterial to alveolar oxygen ratio (a/A ratio) of less than 0.2 or the need for peak inspiratory pressure greater than 35 cm H2O on conventional ventilation. RESULTS Of the 190 patients, 111 (58%) responded to HFOV (HFOV responders), and 79 (42%) were placed on extracorporeal membrane oxygenation (ECMO) after HFOV failed to improve gas exchange (nonresponders). The two groups were similar in gender and birth weight. Factors associated with failure of HFOV to produce a sustained improvement in gas exchange were a diagnosis of congenital diaphragmatic hernia and more severe respiratory compromise as assessed by admission blood gas. Stepwise logistic regression analysis showed that a diagnosis of congenital diaphragmatic hernia/lung hypoplasia (CDH/LH) and the a/A ratio at initiation of and after 6 hours of HFOV were the only significant independent predictors of the need for ECMO. Among all the patients, the presence of CDH/LH or an initial a/A ratio of 0.05 or lower yielded a sensitivity of 74% and specificity of 77% in correctly identifying neonates in whom HFOV failed to produce a sustained improvement in oxygenation. When neonates with CDH/LH were excluded from analysis, the most significant predictor of failure of HFOV was the a/A ratio after 6 hours of HFOV. In neonates without CHD/LH, a 6-hour a/A ratio of 0.08 or lower discriminated responders from nonresponders (ie, treatment with ECMO) with a sensitivity of 77% and specificity of 92%. CONCLUSIONS In our patients, the presence of CDH/LH, severe respiratory failure (a/A ratio 0.05 or lower) at initiation of HFOV, and lack of improvement in oxygenation (a/A ratio 0.08 or lower after 6 hours of HFOV) were associated with failure of HFOV and treatment with ECMO. This information should help other centers to identify neonates who are at the greatest risk for requiring ECMO support and thus allow prompt transfer to an ECMO center.