In this paper, we develop structured tree outflow boundary conditions for modeling the airflow in patient specific human lungs. The utilized structured tree is used to represent the nonimageable vessels beyond the 3D domain. The coupling of the two different scales (1D and 3D) employs a Dirichlet–Neumann approach. The simulations are performed under a variety of conditions such as light breathing and constant flow ventilation (which is characterized by very rapid acceleration and deceleration). All results show that the peripheral vessels significantly impact the pressure, however, the flow is relatively unaffected, reinforcing the fact that the majority of the lung impedance is due to the lower generations rather than the peripheral vessels. Furthermore, simulations of a hypothetical diseased lung (restricted flow in the superior left lobe) under mechanical ventilation show that the mean pressure at the outlets of the 3D domain is about 28% higher. This hypothetical model illustrates potential causes of volutrauma in the human lung and furthermore demonstrates how different clinical scenarios can be studied without the need to assume the unknown flow distribution into the downstream region.