In previous calculations of how the O2 transport system limits [Formula: see text] , it was reasonably assumed that mitochondrial [Formula: see text] ( [Formula: see text] ) could be neglected (set to zero). However, in reality, [Formula: see text] must exceed zero and the red cell to mitochondrion diffusion gradient may therefore be reduced, impairing diffusive transport of O2 and [Formula: see text] . Accordingly, we investigated the influence of [Formula: see text] on these calculations by coupling previously used equations for O2 transport to one for mitochondrial respiration relating mitochondrial [Formula: see text] to [Formula: see text] . This hyperbolic function, characterized by its P50 and V˙MAX, allowed [Formula: see text] to become a model output (rather than set to zero as previously). Simulations using data from exercising normal subjects showed that at [Formula: see text] , [Formula: see text] was usually<1mm Hg, and that the effects on [Formula: see text] were minimal. However, when O2 transport capacity exceeded mitochondrial V˙MAX, or if P50 were elevated, [Formula: see text] often reached double digit values, thereby reducing the diffusion gradient and significantly decreasing [Formula: see text] .