A time-dependent simulation model, based on the Coburn-Forster-Kane equation, was written in Advanced Continuous Simulation Language to predict carboxyhemoglobin (HbCO) formation and dissociation in F-344 rats during and after exposure to 500 parts/million CO for 1 h. Blood-gas analysis and CO-oximetry were performed on samples collected during exposure and off-gassing of CO. Volume displacement plethysmography was used to measure minute ventilation (E) during exposure. CO diffusing capacity in the lung (DL_CO) was also measured. Other model parameters measured in the animals included blood pH, total blood volume, and Hb concentration. Comparisons between model predictions using values for E, DL_CO, and the Haldane coefficient cited in the literature and predictions using measured E, DL_CO, and calculated Haldane coefficient for individual animals were made. General model predictions using values for model parameters derived from the literature agreed with published HbCO values by a factor of 0.987 but failed to simulate experimental data. On average, the general model overpredicted measured HbCO level by nearly 9%. A specific model using the means of measured variables predicted HbCO concentration within a factor of 0.993. When experimentally observed parameter fluctuations were included, the specific model predictions reflected experimental effects on HbCO formation.