Rapid reductions in P_aCO₂ during extracorporeal membrane oxygenation (ECMO) are associated with poor neurologic outcomes. Understanding what factors determine P_aCO₂ may allow a gradual reduction, potentially improving neurologic outcome. A simple and intuitive arithmetic expression was developed, to describe the interactions between the major factors determining P_aCO₂ during venovenous ECMO. This expression was tested using a wide range of input parameters from clinically feasible scenarios. The difference between P_aCO₂ predicted by the arithmetic equation and P_aCO₂ predicted by a more robust and complex in-silico mathematical model, was <10 mm Hg for more than 95% of the scenarios tested. With no CO₂ in the sweep gas, P_aCO₂ is proportional to metabolic CO₂ production and inversely proportional to the “total effective expired ventilation” (sum of alveolar ventilation and oxygenator ventilation). Extracorporeal blood flow has a small effect on P_aCO₂, which becomes more important at low blood flows and high recirculation fractions. With CO₂ in the sweep gas, the increase in P_aCO₂ is proportional to the concentration of CO₂ administered. P_aCO₂ also depends on the fraction of the total effective expired ventilation provided via the oxygenator. This relationship offers a simple intervention to control P_aCO₂ using titration of CO₂ in the sweep gas.