The High-Frequency Intervention Trial was a 10-center randomized clinical trial to test the efficacy and safety of high-frequency oscillatory ventilation (HFO) in the treatment of neonates weighing 750 to 2000 gm; 327 infants were assigned to HFO and 346 to conventional intermittent mechanical ventilation (IMV). Survival and lung morbidity rates were the same in the two groups. Bayley psychometric evaluations and CNS examination were performed at 16 to 24 months of postterm age in 77% of the survivors (185 HFO and 201 IMV). There was no difference in growth or respiratory status at follow-up. Cerebral palsy was diagnosed in 19 (10%) HFO-treated infants and 23 (11%) IMV-treated infants. There was no difference in severity between the two groups. A significantly higher incidence of hydrocephalus (12% vs 6%) was present in the HFO group (p less than 0.05). Bayley index scores greater than 83 were scored in 57% of HFO-treated infants compared with 66% of IMV-treated infants. The proportion of children at follow-up with a normal neuro-developmental status (i.e., Bayley score greater than 83 and no major CNS defect) was significantly less in the HFO than in the IMV group (54 vs 65%; p less than 0.05). Both treatment groups showed a strong association between the presence of grade 3 or 4 intraventricular hemorrhage and the development of major CNS or cognitive defects. No significant long-term beneficial or deleterious effects were demonstrated in the use of HFO versus IMV for the treatment of respiratory failure in low birth weight premature infants, except that there were slightly more neurologic deficits in the HFO group related to the higher proportion of survivors with major intraventricular hemorrhage.