We studied the effect of the interaction between diffusion limitation and alveolar ventilation to perfusion ratio (VA/Q) mismatch in the relation between blood gas partial pressures and cardiac output (Q). The analysis was based on a mathematical model of gas exchange involving two exchanging compartments and a right to left shunt. A system of equations describing alveolar-arterial mass conservation for O2, CO2 and N2 and Bohr integration for O2 and CO2 was interactively solved to find sets of alveolar and blood gas partial pressures fitting input data. Simulations used values compatible with patients in respiratory failure and neonate piglets. Association of (VA/Q) mismatch and diffusion impairment limited the increase of PaO2 with Q. A maximum in the PaO2 vs. Q curve can be attained, further Q increases lead to reductions in PaO2. The effect was accentuated by increasing (VA/Q) and diffusion to perfusion heterogeneity. Combination of (VA/Q) mismatch and diffusion limitation was synergistic leading to greater reductions in PaO2 than expected from simple addition of their independent influences. The findings are compatible with experimental data.