Background. The objective of this study was to determine the intracranial, cardiovascular and respiratory changes induced by conversion to high-frequency oscillator ventilation from conventional mechanical ventilation at increasing airway pressures. Methods: In this study, 11 anaesthetized sheep had invasive cardiovascular and intracranial monitors placed. Lung injury was induced by saline lavage and head injury was induced by inflation of an intracranial balloon catheter. All animals were sequentially converted from conventional mechanical ventilation to high-frequency oscillator ventilation at target mean airway pressures of 16, 22, 28, 34 and 40 cm H2O. The mean airway pressure was achieved by adjusting positive end expiratory pressure while on conventional mechanical ventilation, and continuous distending pressures while on high-frequency oscillator ventilation. Cerebral lactate production, oxygen consumption and venous oximetry were measured and analysed in relation to changes in transcranial Doppler flow velocity. Transcranial Doppler profiles together with other physiological parameters were measured at each airway pressure. Results: Cerebral perfusion pressure was significantly lower during high-frequency oscillator ventilation than during conventional mechanical ventilation (CMV: 45, 34, 22, 6, 9 mmHg vs. HFOV: 33, 20, 19, 5, 5 mmHg at airway pressures mentioned above, P = 0.02). Intracranial pressure and cerebrovascular resistance increased with increasing intrathoracic pressures (P = 0.001). Cerebral metabolic indices demonstrated an initial increase in anaerobic metabolism followed by a decrease in cerebral oxygen consumption progressing to cerebral infarction as intrathoracic pressures were further increased in a stepwise fashion. Arterial PaCO2 increased significantly after converting from conventional mechanical ventilation to high-frequency oscillator ventilation (P = 0.001). However, no difference was observed between conventional mechanical ventilation and high-frequency oscillator ventilation when intracranial pressure, metabolic and transcranial Doppler indices were compared at equivalent mean airway pressures. Conclusions: The use of high positive end expiratory pressure with conventional mechanical ventilation or high continuous distending pressure with high-frequency oscillator ventilation increased intracranial pressure and adversely affected cerebral metabolic indices in this ovine model. Transcranial Doppler is a useful adjunct to Intracranial pressure and intracranial venous saturation monitoring when major changes in ventilation strategy are adopted.