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Using an original, validated, high-fidelity model of pulmonary physiology, we compared the arterial to end-tidal CO2 gradient divided by the arterial CO2 tension (Pa-e′co2/Paco2) with alveolar dead space expressed as a fraction of alveolar tidal volume, calculated in the conventional manner using Fowler’s technique and the Bohr equation: (VDalv/VTalv)Bohr-Fowler. We examined the variability of Pa-e′co2/Paco2 and of (VDalv/VTalv)Bohr-Fowler in the presence of three ventilation-perfusion defects while varying CO2 production (V̇co2), venous admixture, and anatomical dead space fraction (VDanat). Pa-e′co2/Paco2 was approximately 59.5% of (VDalv/VTalv)Bohr-Fowler. During constant alveolar configuration, the factors examined (V̇co2, pulmonary shunt fraction, and VDanat) each caused variation in (VDalv/VTalv)Bohr-Fowler and in Pa-e′co2/Paco2. Induced variation was slightly larger for Pa-e′co2/Paco2 during changes in VDanat, but was similar during variation of venous admixture and V̇co2. Pa-e′co2/Paco2 may be a useful serial measurement in the critically ill patient because all the necessary data are easily obtained and calculation is significantly simpler than for (VDalv/VTalv)Bohr-Fowler.