High-frequency oscillatory ventilation (HFOV) may improve pulmonary outcome in very preterm infants, but the effects on the brain are largely unknown. We hypothesized that early prolonged HFOV compared with low volume positive pressure ventilation (LV-PPV) would not increase the risk of delayed brain growth or injury in a primate model of neonatal chronic lung disease. Baboons were delivered at 127 +/- 1 d gestation (dg; term approximately 185 dg), ventilated for 22-29 d with either LV-PPV (n = 6) or HFOV (n = 5). Gestational controls were delivered at 153 dg (n = 4). Brains were assessed using quantitative histology. Body, brain, and cerebellar weights were lower in both groups of prematurely delivered animals compared with controls; the brain to body weight ratio was higher in HFOV compared with LV-PPV, and the surface folding index was lower in the LV-PPV compared with controls. In both ventilated groups compared with controls, there was an increase in astrocytes and microglia and a decrease in oligodendrocytes (p < 0.05) in the forebrain and a decrease in cerebellar granule cell proliferation (p < 0.01); there was no difference between ventilated groups. LV-PPV and HFOV ventilation in prematurely delivered animals is associated with decreased brain growth and an increase in subtle neuropathologies; HFOV may minimize adverse effects on brain growth.