The role of rescue high-frequency oscillatory ventilation (HFO) in treating very-low-birth-weight neonates with severe respiratory failure in relation to neurodevelopmental outcome has not been evaluated. We performed a retrospective cohort study on 21 patients (out of 52 consecutively admitted preterm neonates with gestational age < or = 30 weeks and birth weight < or = 1.250 g; mortality rate 60%) rescued with HFO between October 1988 and August 1993. Neurodevelopment, including Bayley Scales in Infant Development, was assessed at 12-61 (mean 28.5) months adjusted age. Thirteen normal (scores better than 2 SD below mean, and no sensory or motor disability) (62%) and neurodevelopmentally disabled children (38%) survived more than 1 year for developmental assessment. The mental and performance developmental indices were 94 (78-117) and 89 (68-110), and 63 (49-102) and 49 for the 13 normal and 8 disabled children, respectively (both p < 0.05). The incidence of bronchopulmonary dysplasia, intraventricular hemorrhage (IVH; grade 3 or 4), growth retardation, developmental scores and disabilities of these 21 HFO survivors were not significantly different from that of a birth-weight- and gestational-age-matched comparison group. While all HFO survivors had significant improvement in oxygenation 12 and 24 h after starting HFO, FiO2 and the alveolar-arterial oxygen gradient (A-aDO2) decreased significantly 1 h after starting HFO in survivors with normal neurodevelopmental outcome. The lack of initial response to HFO (20% decrease in A-aDO2 1 h after starting HFO) and the presence of grade 3 or 4 IVH predicted neurodevelopmental disability with a sensitivity of 63%, a specificity of 100%, and positive and negative predictive values of 100 and 81%, respectively. We concluded that HFO could be used as a rescue treatment in sick preterm neonates. The lack of early improvement in oxygenation and the presence of grade 3 or 4 IVH can predict adverse early childhood neurodevelopment in such neonates.