Uptake of environmental carbon monoxide (CO) via the lungs raises the CO content of blood and of myoglobin (Mb)-containing tissues, but the blood-to-tissue diffusion coefficient for CO (DmCO) and tissue CO content are not easily measurable in humans. We used a multicompartment mathematical model to predict the effects of different values of DmCO on the time courses and magnitudes of CO content of blood and Mb-containing tissues when various published experimental studies were simulated. The model enhances our earlier model by adding mass balance equations for oxygen and by dividing the muscle compartment into two subcompartments. We found that several published experimental findings are compatible with either fast or slow rates of blood-tissue transfer of CO, whereas others are only compatible with slow rates of tissue uptake of CO. We conclude that slow uptake is most consistent with all of the experimental data. Slow uptake of CO by tissue is primarily due to the very small blood-to-tissue partial pressure gradients for CO.