The determination of O₂ consumption by using arteriovenous O₂ content differences is dependent on accurate oxyhemoglobin saturation measurements. Because swine are a common experimental species, we describe the validation of CO-oximeter for porcine-specific oxyhemoglobin saturation. After developing a nonlinear mathematical model of the porcine oxyhemoglobin saturation curve, we made 366 porcine oxyhemoglobin saturation determinations with a calibrated blood-gas analyzer and a porcine-specific CO-oximeter. There was a high degree of correlation with minimal variability (r² = 0.99, SE of the estimate = 5.2%) between the mathematical model and the porcine-specific CO-oximeter measurements. Bland-Altman comparison showed that the CO-oximeter measurements were biased slightly lower (0.4 vol%), and the limits of agreement (±2 SD) were 0.7 and 1.5 vol%. This is in contrast to a 10-20 vol% error if human-specific methods were used. The results show excellent agreement between the nonlinear model and CO-oximeter for porcine-specific oxyhemoglobin saturation measurements. In contrast, comparison of the porcine-specific oxyhemoglobin saturations with saturations obtained by using human methods highlights the necessity of species-specific measurement methodology.