Analyses of diffusion limitation of pulmonary O2 exchange have stressed that alveolar PO2 (PAO2) is one of the most important factors to consider, but recent reports suggest that PAO2 is important only insofar as it determines the effective slope of the O2 dissociation curve. If this slope is the critical factor, mixed venous PO2 (PVO2) should also be important. This notion was examined in theoretical calculations of oxygenation along the capillary in a homogeneous lung model of normal diffusing capacity. For PAO2 = 100 torr, half-time of rise of PO2 between PVO2 and PAO2 (T 1/2) increased from 0.09 s (PVO2 = 50) to 0.32 s (PVO2 = 10), while for PAO2 = 60, T 1/2 increased from 0.18 s (PVO2 = 50) to 0.43 s (PVO2 = 10). At PAO2 = 60, diffusion equilibration after 0.75 s was virtually complete if PVO2 greater than or equal to 40 torr, but was only 80% complete for PVO2 = 10. These calculations show that at any given PAO2, PVO2 has considerable influence on the rate of diffusion equilibration of O2. Thus, situations in which PVO2 is low (e.g. when cardiac output is low in relation to O2 uptake) are associated with considerably increased vulnerability of O2 exchange to diffusion limitation, other factors remaining unchanged.