The primary objective of this study was to investigate the pharmacokinetics of inhaled argon in young pigs using mechanical ventilation. Also a physiologically based model of argon pharmacokinetics (PBPK) is validated with human data for xenon from the literature and the new data from juvenile pigs. The inherent difficulty in performing pharmacokinetics studies of argon makes the use of the PBPK model especially relevant. The model is used to investigate argon pharmacokinetics for adult and neonate applications. Juvenile pigs ( n = 4) were anesthetized, submitted to endotracheal intubation, and mechanical ventilation using a conventional ventilator. Argon inhalation was achieved by switching the animal from the first mechanical ventilator (with air/oxygen) to a second one that was supplied with 75% argon and 25% oxygen from premixed gas cylinders. This administration yielded blood samples that were analyzed using a quadrupole based technique for determining argon concentration. The range of blood:gas partition coefficient corresponding to the average measured Cmax of 190–872 μM is 0.005–0.022. Based on the average curve, T 1/2 = 75 seconds. The PBPK is shown to be in general agreement with the experimental data in pigs. Inhaled argon administration exhibited an on-off nature such that AUC was proportional to administration time. Confidence in the PBPK model and the remarkably robust and stable on-off nature of argon pharmacokinetics, notwithstanding intersubject variability and comorbidity, suggests that inhaled argon could readily be applied to any treatment regime.