Contrast-enhanced magnetic resonance imaging (MRI) measurement of cerebral perfusion is a diagnostic procedure increasingly gaining access to clinical practice not only in spontaneously breathing patients but also in mechanically ventilated patients. Effects of increased mean airway pressure on cerebral perfusion are entirely possible. Therefore, the present study used continuous positive airway pressure (CPAP) (12 cm H2O) to study the effects of increased mean airway pressure on cerebral perfusion in volunteers. CPAP significantly reduced regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) but increased regional mean transit time (rMTT) and regional cerebrovascular resistance (rCVR). Active vasoconstriction (e.g., arterial) and/or passive compression of capillary and/or venous vessel areas are the most likely underlying mechanisms. The number of interhemispheric differences in rCBF, rCBV, rMTT, and rCVR found at baseline rose when mean airway pressure was increased. These results, although obtained in volunteers, should be taken into consideration for the interpretation of contrast-enhanced MRI perfusion measurements in mechanically ventilated patients with an increased positive airway pressure.