Multiple studies have shown that cerebral tissue oxygen saturation ( Sct O 2 ) is decreased after phenylephrine treatment. We hypothesized that the negative impact of phenylephrine administration on Sct O 2 is affected by arterial blood carbon dioxide partial pressure (PaCO2) because CO2 is a powerful modulator of cerebrovascular tone. In 14 anaesthetized healthy patients, i.v. phenylephrine bolus was administered to increase the mean arterial pressure ∼20–30% during hypocapnia, normocapnia, and hypercapnia. Sct O 2 and cerebral blood volume (CBV) were measured using frequency domain near-infrared spectroscopy, a quantitative technology. Data collection occurred before and after each treatment. Phenylephrine caused a significant decrease in Sct O 2 during hypocapnia [Δ Sct O 2 =−3.4 (1.5)%, P<0.001], normocapnia [Δ Sct O 2 =−2.4 (1.5)%, P<0.001], and hypercapnia [Δ Sct O 2 =−1.4 (1.5)%, P<0.01]. Decreases in Sct O 2 were significantly different between hypocapnia, normocapnia, and hypercapnia (P<0.001). Phenylephrine also caused a significant decrease in CBV during hypocapnia (P<0.01), but not during normocapnia or hypercapnia. The negative impact of phenylephrine treatment on Sct O 2 and CBV is intensified during hypocapnia while blunted during hypercapnia.