Accurate measurements of arterial P(CO(2)) (P(a,CO(2))) currently require blood sampling because the end-tidal P(CO(2)) (P(ET,CO(2))) of the expired gas often does not accurately reflect the mean alveolar P(CO(2)) and P(a,CO(2)). Differences between P(ET,CO(2)) and P(a,CO(2)) result from regional inhomogeneities in perfusion and gas exchange. We hypothesized that breathing via a sequential gas delivery circuit would reduce these inhomogeneities sufficiently to allow accurate prediction of P(a,CO(2)) from P(ET,CO(2)). We tested this hypothesis in five healthy middle-aged men by comparing their P(ET,CO(2)) values with P(a,CO(2)) values at various combinations of P(ET,CO(2)) (between 35 and 50 mmHg), P(O(2)) (between 70 and 300 mmHg), and breathing frequencies (f; between 6 and 24 breaths min(-1)). Once each individual was in a steady state, P(a,CO(2)) was collected in duplicate by consecutive blood samples to assess its repeatability. The difference between P(ET,CO(2)) and average P(a,CO(2)) was 0.5 +/- 1.7 mmHg (P = 0.53; 95% CI -2.8, 3.8 mmHg) whereas the mean difference between the two measurements of P(a,CO(2)) was -0.1 +/- 1.6 mmHg (95% CI -3.7, 2.6 mmHg). Repeated measures ANOVAs revealed no significant differences between P(ET,CO(2)) and P(a,CO(2)) over the ranges of P(O(2)), f and target P(ET,CO(2)). We conclude that when breathing via a sequential gas delivery circuit, P(ET,CO(2)) provides as accurate a measurement of P(a,CO(2)) as the actual analysis of arterial blood.