To investigate differences in orotracheal (OT) and nasotracheal (NT) intubation for ventilatory assistance, we randomly assigned 91 neonates to be intubated via either of the two routes: 46 infants were assigned to the OT group and 45 infants were assigned to the NT group. Inability to intubate the nostril in three neonates, and respiratory or cardiac instability during attempted NT intubation in three neonates, resulted in the assignment of 52 infants to the OT group and 39 infants to the NT group; patients in both groups were of comparable size, sex, and clinical problems. Initial malposition of the endotracheal tube and need to retape, reposition, or replace the tube during the mean duration of intubation of 247 +/- 42 hours for the OT group and 273 +/- 57 hours for the NT group were similar. Daily Gram stains of tracheal aspirates showed that inflammation (greater than or equal to ten polymorphonuclear cells per 400 power fields) was common (51% OT group, 53% NT group). Cultures grew potential pathogens in 37% of the patients from the OT group and 31% of the NT group. There was no difference in the clinical or radiologic incidence of pneumonia. Postextubation problems were comparable: atelectasis, 48% OT and 59% NT; stridor, 15% OT and 26% NT. OT intubation may be preferred for prolonged ventilatory assistance in neonates because of the relative ease of initial intubation.