The standard flight level for commercial airliners is ∼12 km (40 kft; air pressure: ∼ 200 hPa), the maximum certification altitude of modern airliners may be as high as 43-45 kft. Loss of structural integrity of an airplane may result in sudden depressurization of the cabin potentially leading to hypoxia with loss of consciousness of the pilots. Specialized breathing masks supply the pilots with oxygen. The aim of this study was to experimentally simulate such sudden depressurization to maximum design altitude in a pressure chamber while measuring the arterial and brain oxygenation saturation (SaO(2) and StO(2)) of the pilots. Ten healthy subjects with a median age of 50 (range 29-70) years were placed in a pressure chamber, breathing air from a cockpit mask. Pressure was reduced from 753 to 148 hPa within 20 s, and the test mask was switched to pure O(2) within 2 s after initiation of depressurization. During the whole procedure SaO(2) and StO(2) were measured by pulse oximetry, respectively near-infrared spectroscopy (NIRS; in-house built prototype) of the left frontal cortex. During the depressurization the SaO(2) dropped from median 93% (range 91-98%) to 78% (62-92%) by 16% (6-30%), while StO(2) decreased from 62% (47-67%) to 57% (43-62%) by 5% (3-14%). Considerable drops in oxygenation were observed during sudden depressurization. The inter-subject variability was high, for SaO(2) depending on the subjects' ability to preoxygenate before the depressurization. The drop in StO(2) was lower than the one in SaO(2) maybe due to compensation in blood flow.