Objective: To measure the impact of changes in the fraction of inspired oxygen (FiO₂) on systemic and cerebral oxygen supply in gas and liquid ventilated healthy animals. Design: Interventional prospective animal study. Setting: University research laboratory. Participants: Ten healthy, new-born piglets. Interventions: Variations in FiO₂ during conventional mechanical ventilation (CMV) followed by partial liquid ventilation (PLV) with two different filling volumes of PF 5080 (10 vs. 30 ml/kg). Measurements and results: Arterial blood gases were obtained 15 min after changing FiO₂ and concentrations of cerebral oxygenated and total hemoglobin were determined with near infrared spectroscopy. During CMV an increase in FiO₂ 1.0 was associated with a constant rise in PaO ₂ but only a small increase in the cerebral concentration of oxygenated Hb. Initiation of PLV (at FiO₂ of 1.0) caused a rapid drop in PaO₂ towards values that were similar to CMV at FiO ₂ of 0.5. At FiO₂ of 0.5 a reduction in oxygenated Hb was found in the 30 ml/kg filling group. Complete filling of the lungs with PFC caused a significant drop in total cerebral Hb concentration. Conclusions: According to our data, PLV in healthy lungs should be performed with a FiO ₂ of 1.0 and a small filling volume to avoid deterioration in cerebral oxygen supply.