Objectives: To validate a mathematical model using porous media theory for alveolar CO 2 determination in ventilated patients. Design: Mathematical modeling study with prospective clinical validation to simulate CO 2 exchange from bloodstream to airway entrance. Setting: ICU. Patients: Thirteen critically ill patients without chronic or acute lung disease. Interventions: None. Measurements and Main Results: Model outcomes compared with patient data showed correlations for end-tidal CO 2 (EtCO 2 ), area under the CO 2 curve, and Pa CO 2 of 0.918, 0.954, and 0.995. Determination coefficients ( R 2 ) were 0.843, 0.910, and 0.990, indicating precision and predictive power. Conclusions: The mathematical model shows potential in pulmonary critical care. Although promising, practical application demands further validation, clinician training, and patient-specific adjustments. The path to clinical use will be iterative, involving validation and education.