A breath-holding method for measuring the PCO2 of mixed venous blood has been developed. Two gas mixtures, 100 per cent O2 and 12 per cent CO2 in O2, were inspired, and the expired gas was analyzed after 5 and 15 sec of breathholding. The oxygenated mixed venous PCO2 was calculated using an exponential equation. The method was applied in healthy subjects, patients with lung disease, and unconscious mechanically ventilated patients. The mixed venous PCO2 correlated well with arterial PCO2 (r = 0.96), the PCO2 obtained by rebreathing (r = 0.97), and the PCO2 in blood drawn from the pulmonary artery (r = 0.97). The method is noninvasive, has a low coefficient of variance, and allows arterial PCO2 to be estimated by multiplying the breath-holding mixed venous PCO2 by 0.8.