Computational fluid dynamics (CFD) simulations were performed using large-scale models of the human lung airway and unsteady periodic breathing conditions. The computational domain included fully coupled representations of the orotracheal region and large conducting zone up to generation four (G4) obtained from patient-specific CT data, and the small conducting zone (to the 16th generation) obtained from a stochastically generated airway tree with statistically realistic morphological characteristics. A reduced-geometry airway model was used, in which several airway branches in each generation were truncated, and only select flow paths were retained to the 16th generation. The inlet and outlet flow boundaries corresponded to the oral opening, the physical inlet/outlet boundaries at the terminal bronchioles, and the unresolved airway boundaries created from the truncation procedure. The total flow rate was specified according to the expected ventilation pattern for a healthy adult male, which was supplied by the whole-body modeling software HumMod. The unsteady mass flow distribution at the distal boundaries was prescribed based on a preliminary steady-state simulation with an applied flow rate equal to the average flow rate during the inhalation phase of the breathing cycle. In contrast to existing studies, this approach allows fully coupled simulation of the entire conducting zone, with no need to specify distal mass flow or pressure boundary conditions a priori, and without the use of impedance or one-dimensional (1D) flow models downstream of the truncated boundaries. The results show that: (1) physiologically realistic flow is obtained in the model, in terms of cyclic mass conservation and approximately uniform pressure distribution in the distal airways; (2) the predicted alveolar pressure is in good agreement with correlated experimental data; and (3) the use of reduced-order geometry modeling allows accurate and efficient simulation of large-scale breathing lung flow, provided care is taken to use a physiologically realistic geometry and to properly address the unsteady boundary conditions.