Objectives. Optimizing cerebral oxygenation is of paramount importance in certain intraoperative situations. There is, however, a paucity of published data pertaining to changes in cerebral oxygenation seen with increases in the inspired fraction of oxygen (Fio2) or end-tidal carbon dioxide (Petco2) in anesthetized patients without vascular disease. Here we tested the hypothesis that changes in Fio2 or Petco2 correlate to a significant change in regional cerebral oxygenation (rSO2) in anesthetized patients without vascular disease. Methods. This was a prospective pilot study approved by the IRB. We measured rSO2 using the INVOS 5100B monitor in ten anesthetized patients. Patients were excluded if they had a history of or risk factors for vascular disease, suffered from respiratory failure, or did not speak English. Following induction of anesthesia and intubation, Fio2 and minute ventilation were sequentially adjusted. At each set point, rSO2 was recorded and arterial blood gas analysis was performed. Each patient acted as their own control. A paired-sample t test was used to evaluate the change in rSO2 resultant upon each intervention. Results. The baseline rSO2 was measured with patients awake, breathing room air and varied between 48 and 72%. While maintaining Petco2 in the range 30–35 mmHg, rSO2 was 8% higher when 100% oxygen was delivered compared to Fio2 30% (P = 0.021). While maintaining Petco2 in the range 40–45 mmHg, rSO2 was 7% higher when 100% oxygen is delivered compared to Fio2 30% (P = 0.032). While maintaining Fio2 at 100%, rSO2 was 2% higher when Petco2 was in the range 40–45 mmHg compared to Petco2 30–35 mmHg (P = 0.017). While maintaining Fio2 at 30%, rSO2 was not statistically different between PECO2 40–45 mmHg and Petco2 30–35 mmHg. Conclusions. Modulating oxygenation and ventilation in anesthetized patients without vascular disease leads to measurable changes in rSO2.