The feasibility of computational fluid dynamics (CFD) to evaluate airflow characteristics in different head and neck positions has not been established. This study compared the changes in volume and airflow behavior of the upper airway by CFD simulation to predict the influence of anatomical and physiological airway changes due to different head-neck positions on mechanical ventilation. One awake volunteer with no risk of difficult airway underwent computed tomography in neutral position, extension position (both head and neck extended), and sniffing position (head extended and neck flexed). Three-dimensional airway models of the upper airway were reconstructed. The total volume (V) and narrowest area (A_min) of the airway models were measured. CFD simulation with an Spalart-Allmaras model was performed to characterize airflow behavior in neutral, extension, and sniffing positions of closed-mouth and open-mouth ventilation. The comparison result for V was neutral <extension≈sniffing, and for A_min was neutral<extension<sniffing. A_min in sniffing position was nearly 3.0 times that in neutral position and 1.7 times that in extension position. The pressure drop and velocity increasing were more obvious in neutral than sniffing or extension position at the same airflow rate. In sniffing position, pressure differences decreased and velocity remained almost constant. Recirculation airflow was generated near the subglottic region in neutral and extension positions. Sniffing position improves airway patency by increasing airway volume and decreasing airway resistance, suggesting that sniffing position may be the optimal choice for mask ventilation.