Transcutaneous monitoring of carbon dioxide (CO2) has been proposed for use in physiological monitoring of tactical jet aircrew because in some clinical settings it provides useful information about control of arterial CO2 partial pressure. End tidal monitoring in a laboratory setting is known to give high-fidelity estimates of arterial CO2 partial pressure (PCO2). The correspondence between end-tidal (PETCO2) and transcutaneous (tcPCO2) measures of PCO2 was examined under conditions of hyperoxia and hypoxia in healthy volunteers in a laboratory. Rest and exercise, skin heating and cooling, hyperventilation, and induced CO2 retention were employed. Resting measurements at or near normoxia, and exercise measurements during breathing of 40% O2 were also examined. Bland-Altman analysis of tcPCO2 and PETCO2 showed that the two were equivalent only during normoxic resting measurements. Regression analysis indicated that tissue PO2 measured as transcutaneous PO2 (tcPO2) is an important explanatory variable for tcPCO2 in addition to PETCO2, and that local skin temperature also has an effect. Additionally, prolonged sitting while breathing 100% O2 and hypoxic exercise caused PETCO2 to deviate from PaCO2. Thus, tcPCO2 is not useful as even a trend indicator for arterial PCO2 in the highly dynamic tactical jet aircraft environment. PETCO2 is also not a good indicator of CO2 status in pilots who breathe nearly 100% O2.